Nucleotide Excision Repair (Homo sapiens)
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Description
Nucleotide excision repair (NER) was first described in the model organism E. coli in the early 1960s as a process whereby bulky base damage is enzymatically removed from DNA, facilitating the recovery of DNA synthesis and cell survival. Deficient NER processes have been identified from the cells of cancer-prone patients with different variants of xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne's syndrome. The XP cells exhibit an ultraviolet radiation hypersensitivity that leads to a hypermutability response to UV, offering a direct connection between deficient NER, increased mutation rate, and cancer. While the NER pathway in prokaryotes is unique, the pathway utilized in yeast and higher eukaryotes is highly conserved.
NER is involved in the repair of bulky adducts in DNA, such as UV-induced photo lesions (both 6-4 photoproducts (6-4 PPDs) and cyclobutane pyrimidine dimers (CPDs)), as well as chemical adducts formed from exposure to aflatoxin, benzopyrene and other genotoxic agents. Specific proteins have been identified that participate in base damage recognition, cleavage of the damaged strand on both sides of the lesion, and excision of the oligonucleotide bearing the lesion. Reparative DNA synthesis and ligation restore the strand to its original state.
NER consists of two related pathways called global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER). The pathways differ in the way in which DNA damage is initially recognized, but the majority of the participating molecules are shared between these two branches of NER. GG-NER is transcription-independent, removing lesions from non-coding DNA strands, as well as coding DNA strands that are not being actively transcribed. TC-NER repairs damage in transcribed strands of active genes.
Several of the proteins involved in NER are key components of the basal transcription complex TFIIH. An ubiquitin ligase complex composed of DDB1, CUL4A or CUL4B and RBX1 participates in both GG-NER and TC-NER, implying an important role of ubiquitination in NER regulation. The establishment of mutant mouse models for NER genes and other DNA repair-related genes has been useful in demonstrating the associations between NER defects and cancer.
For past and recent reviews of nucleotide excision repair, please refer to Lindahl and Wood 1998, Friedberg et al. 2002, Christmann et al. 2003, Hanawalt and Spivak 2008, Marteijn et al. 2014). View original pathway at:Reactome.
NER is involved in the repair of bulky adducts in DNA, such as UV-induced photo lesions (both 6-4 photoproducts (6-4 PPDs) and cyclobutane pyrimidine dimers (CPDs)), as well as chemical adducts formed from exposure to aflatoxin, benzopyrene and other genotoxic agents. Specific proteins have been identified that participate in base damage recognition, cleavage of the damaged strand on both sides of the lesion, and excision of the oligonucleotide bearing the lesion. Reparative DNA synthesis and ligation restore the strand to its original state.
NER consists of two related pathways called global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER). The pathways differ in the way in which DNA damage is initially recognized, but the majority of the participating molecules are shared between these two branches of NER. GG-NER is transcription-independent, removing lesions from non-coding DNA strands, as well as coding DNA strands that are not being actively transcribed. TC-NER repairs damage in transcribed strands of active genes.
Several of the proteins involved in NER are key components of the basal transcription complex TFIIH. An ubiquitin ligase complex composed of DDB1, CUL4A or CUL4B and RBX1 participates in both GG-NER and TC-NER, implying an important role of ubiquitination in NER regulation. The establishment of mutant mouse models for NER genes and other DNA repair-related genes has been useful in demonstrating the associations between NER defects and cancer.
For past and recent reviews of nucleotide excision repair, please refer to Lindahl and Wood 1998, Friedberg et al. 2002, Christmann et al. 2003, Hanawalt and Spivak 2008, Marteijn et al. 2014). View original pathway at:Reactome.
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- Dinant C, Ampatziadis-Michailidis G, Lans H, Tresini M, Lagarou A, Grosbart M, Theil AF, van Cappellen WA, Kimura H, Bartek J, Fousteri M, Houtsmuller AB, Vermeulen W, Marteijn JA.; ''Enhanced chromatin dynamics by FACT promotes transcriptional restart after UV-induced DNA damage.''; PubMed Europe PMC Scholia
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- Min JH, Pavletich NP.; ''Recognition of DNA damage by the Rad4 nucleotide excision repair protein.''; PubMed Europe PMC Scholia
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- Sollier J, Stork CT, García-Rubio ML, Paulsen RD, Aguilera A, Cimprich KA.; ''Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability.''; PubMed Europe PMC Scholia
- Mourgues S, Gautier V, Lagarou A, Bordier C, Mourcet A, Slingerland J, Kaddoum L, Coin F, Vermeulen W, Gonzales de Peredo A, Monsarrat B, Mari PO, Giglia-Mari G.; ''ELL, a novel TFIIH partner, is involved in transcription restart after DNA repair.''; PubMed Europe PMC Scholia
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- Balajee AS, May A, Dianova I, Bohr VA.; ''Efficient PCNA complex formation is dependent upon both transcription coupled repair and genome overall repair.''; PubMed Europe PMC Scholia
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- Wakasugi M, Shimizu M, Morioka H, Linn S, Nikaido O, Matsunaga T.; ''Damaged DNA-binding protein DDB stimulates the excision of cyclobutane pyrimidine dimers in vitro in concert with XPA and replication protein A.''; PubMed Europe PMC Scholia
- Fei J, Chen J.; ''KIAA1530 protein is recruited by Cockayne syndrome complementation group protein A (CSA) to participate in transcription-coupled repair (TCR).''; PubMed Europe PMC Scholia
- Sugasawa K, Akagi J, Nishi R, Iwai S, Hanaoka F.; ''Two-step recognition of DNA damage for mammalian nucleotide excision repair: Directional binding of the XPC complex and DNA strand scanning.''; PubMed Europe PMC Scholia
- Tsodikov OV, Ivanov D, Orelli B, Staresincic L, Shoshani I, Oberman R, Schärer OD, Wagner G, Ellenberger T.; ''Structural basis for the recruitment of ERCC1-XPF to nucleotide excision repair complexes by XPA.''; PubMed Europe PMC Scholia
- Sarker AH, Tsutakawa SE, Kostek S, Ng C, Shin DS, Peris M, Campeau E, Tainer JA, Nogales E, Cooper PK.; ''Recognition of RNA polymerase II and transcription bubbles by XPG, CSB, and TFIIH: insights for transcription-coupled repair and Cockayne Syndrome.''; PubMed Europe PMC Scholia
- Rossignol M, Kolb-Cheynel I, Egly JM.; ''Substrate specificity of the cdk-activating kinase (CAK) is altered upon association with TFIIH.''; PubMed Europe PMC Scholia
- Mathieu N, Kaczmarek N, Naegeli H.; ''Strand- and site-specific DNA lesion demarcation by the xeroderma pigmentosum group D helicase.''; PubMed Europe PMC Scholia
- Zhang X, Horibata K, Saijo M, Ishigami C, Ukai A, Kanno S, Tahara H, Neilan EG, Honma M, Nohmi T, Yasui A, Tanaka K.; ''Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair.''; PubMed Europe PMC Scholia
- Poulsen SL, Hansen RK, Wagner SA, van Cuijk L, van Belle GJ, Streicher W, Wikström M, Choudhary C, Houtsmuller AB, Marteijn JA, Bekker-Jensen S, Mailand N.; ''RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response.''; PubMed Europe PMC Scholia
- Fang L, Wang X, Yamoah K, Chen PL, Pan ZQ, Huang L.; ''Characterization of the human COP9 signalosome complex using affinity purification and mass spectrometry.''; PubMed Europe PMC Scholia
- Jawhari A, Lainé JP, Dubaele S, Lamour V, Poterszman A, Coin F, Moras D, Egly JM.; ''p52 Mediates XPB function within the transcription/repair factor TFIIH.''; PubMed Europe PMC Scholia
- Epshtein V, Kamarthapu V, McGary K, Svetlov V, Ueberheide B, Proshkin S, Mironov A, Nudler E.; ''UvrD facilitates DNA repair by pulling RNA polymerase backwards.''; PubMed Europe PMC Scholia
- Moser J, Kool H, Giakzidis I, Caldecott K, Mullenders LH, Fousteri MI.; ''Sealing of chromosomal DNA nicks during nucleotide excision repair requires XRCC1 and DNA ligase III alpha in a cell-cycle-specific manner.''; PubMed Europe PMC Scholia
- Akita M, Tak YS, Shimura T, Matsumoto S, Okuda-Shimizu Y, Shimizu Y, Nishi R, Saitoh H, Iwai S, Mori T, Ikura T, Sakai W, Hanaoka F, Sugasawa K.; ''SUMOylation of xeroderma pigmentosum group C protein regulates DNA damage recognition during nucleotide excision repair.''; PubMed Europe PMC Scholia
- Oksenych V, Bernardes de Jesus B, Zhovmer A, Egly JM, Coin F.; ''Molecular insights into the recruitment of TFIIH to sites of DNA damage.''; PubMed Europe PMC Scholia
- Ahel D, Horejsí Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I, Flynn H, Skehel M, West SC, Jackson SP, Owen-Hughes T, Boulton SJ.; ''Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1.''; PubMed Europe PMC Scholia
- Coin F, Marinoni JC, Rodolfo C, Fribourg S, Pedrini AM, Egly JM.; ''Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH.''; PubMed Europe PMC Scholia
- Reardon JT, Ge H, Gibbs E, Sancar A, Hurwitz J, Pan ZQ.; ''Isolation and characterization of two human transcription factor IIH (TFIIH)-related complexes: ERCC2/CAK and TFIIH.''; PubMed Europe PMC Scholia
- Groisman R, Groisman R, Kuraoka I, Chevallier O, Gaye N, Magnaldo T, Tanaka K, Kisselev AF, Harel-Bellan A, Nakatani Y.; ''CSA-dependent degradation of CSB by the ubiquitin-proteasome pathway establishes a link between complementation factors of the Cockayne syndrome.''; PubMed Europe PMC Scholia
- Vermeulen W, Fousteri M.; ''Mammalian transcription-coupled excision repair.''; PubMed Europe PMC Scholia
- Ogi T, Limsirichaikul S, Overmeer RM, Volker M, Takenaka K, Cloney R, Nakazawa Y, Niimi A, Miki Y, Jaspers NG, Mullenders LH, Yamashita S, Fousteri MI, Lehmann AR.; ''Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells.''; PubMed Europe PMC Scholia
- Donahue BA, Yin S, Taylor JS, Reines D, Hanawalt PC.; ''Transcript cleavage by RNA polymerase II arrested by a cyclobutane pyrimidine dimer in the DNA template.''; PubMed Europe PMC Scholia
- Groisman R, Groisman R, Polanowska J, Kuraoka I, Sawada J, Saijo M, Drapkin R, Kisselev AF, Tanaka K, Nakatani Y.; ''The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage.''; PubMed Europe PMC Scholia
- Moser J, Volker M, Kool H, Alekseev S, Vrieling H, Yasui A, van Zeeland AA, Mullenders LH.; ''The UV-damaged DNA binding protein mediates efficient targeting of the nucleotide excision repair complex to UV-induced photo lesions.''; PubMed Europe PMC Scholia
- Zotter A, Luijsterburg MS, Warmerdam DO, Ibrahim S, Nigg A, van Cappellen WA, Hoeijmakers JH, van Driel R, Vermeulen W, Houtsmuller AB.; ''Recruitment of the nucleotide excision repair endonuclease XPG to sites of UV-induced dna damage depends on functional TFIIH.''; PubMed Europe PMC Scholia
- Nishi R, Okuda Y, Watanabe E, Mori T, Iwai S, Masutani C, Sugasawa K, Hanaoka F.; ''Centrin 2 stimulates nucleotide excision repair by interacting with xeroderma pigmentosum group C protein.''; PubMed Europe PMC Scholia
- Perez-Oliva AB, Lachaud C, Szyniarowski P, Muñoz I, Macartney T, Hickson I, Rouse J, Alessi DR.; ''USP45 deubiquitylase controls ERCC1-XPF endonuclease-mediated DNA damage responses.''; PubMed Europe PMC Scholia
- Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET.; ''Characterization of a second member of the sentrin family of ubiquitin-like proteins.''; PubMed Europe PMC Scholia
- Nakazawa Y, Sasaki K, Mitsutake N, Matsuse M, Shimada M, Nardo T, Takahashi Y, Ohyama K, Ito K, Mishima H, Nomura M, Kinoshita A, Ono S, Takenaka K, Masuyama R, Kudo T, Slor H, Utani A, Tateishi S, Yamashita S, Stefanini M, Lehmann AR, Yoshiura K, Ogi T.; ''Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.''; PubMed Europe PMC Scholia
- Wittschieben BØ, Iwai S, Wood RD.; ''DDB1-DDB2 (xeroderma pigmentosum group E) protein complex recognizes a cyclobutane pyrimidine dimer, mismatches, apurinic/apyrimidinic sites, and compound lesions in DNA.''; PubMed Europe PMC Scholia
- Wakasugi M, Kasashima H, Fukase Y, Imura M, Imai R, Yamada S, Cleaver JE, Matsunaga T.; ''Physical and functional interaction between DDB and XPA in nucleotide excision repair.''; PubMed Europe PMC Scholia
- He Z, Henricksen LA, Wold MS, Ingles CJ.; ''RPA involvement in the damage-recognition and incision steps of nucleotide excision repair.''; PubMed Europe PMC Scholia
- Volker M, Moné MJ, Karmakar P, van Hoffen A, Schul W, Vermeulen W, Hoeijmakers JH, van Driel R, van Zeeland AA, Mullenders LH.; ''Sequential assembly of the nucleotide excision repair factors in vivo.''; PubMed Europe PMC Scholia
- Kapetanaki MG, Guerrero-Santoro J, Bisi DC, Hsieh CL, Rapić-Otrin V, Levine AS.; ''The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites.''; PubMed Europe PMC Scholia
- Hofmann RM, Pickart CM.; ''Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair.''; PubMed Europe PMC Scholia
- Sarkar S, Kiely R, McHugh PJ.; ''The Ino80 chromatin-remodeling complex restores chromatin structure during UV DNA damage repair.''; PubMed Europe PMC Scholia
- Mocquet V, Lainé JP, Riedl T, Yajin Z, Lee MY, Egly JM.; ''Sequential recruitment of the repair factors during NER: the role of XPG in initiating the resynthesis step.''; PubMed Europe PMC Scholia
- Mathieu N, Kaczmarek N, Rüthemann P, Luch A, Naegeli H.; ''DNA quality control by a lesion sensor pocket of the xeroderma pigmentosum group D helicase subunit of TFIIH.''; PubMed Europe PMC Scholia
- Giglia-Mari G, Giglia-Mari G, Coin F, Ranish JA, Hoogstraten D, Theil A, Wijgers N, Jaspers NG, Raams A, Argentini M, van der Spek PJ, Botta E, Stefanini M, Egly JM, Aebersold R, Hoeijmakers JH, Vermeulen W.; ''A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A.''; PubMed Europe PMC Scholia
- Fischer ES, Scrima A, Böhm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thomä NH.; ''The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation.''; PubMed Europe PMC Scholia
- Staresincic L, Fagbemi AF, Enzlin JH, Gourdin AM, Wijgers N, Dunand-Sauthier I, Giglia-Mari G, Giglia-Mari G, Clarkson SG, Vermeulen W, Schärer OD.; ''Coordination of dual incision and repair synthesis in human nucleotide excision repair.''; PubMed Europe PMC Scholia
- Camenisch U, Träutlein D, Clement FC, Fei J, Leitenstorfer A, Ferrando-May E, Naegeli H.; ''Two-stage dynamic DNA quality check by xeroderma pigmentosum group C protein.''; PubMed Europe PMC Scholia
- de Laat WL, Appeldoorn E, Sugasawa K, Weterings E, Jaspers NG, Hoeijmakers JH.; ''DNA-binding polarity of human replication protein A positions nucleases in nucleotide excision repair.''; PubMed Europe PMC Scholia
- Takedachi A, Saijo M, Tanaka K.; ''DDB2 complex-mediated ubiquitylation around DNA damage is oppositely regulated by XPC and Ku and contributes to the recruitment of XPA.''; PubMed Europe PMC Scholia
- Fitch ME, Nakajima S, Yasui A, Ford JM.; ''In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product.''; PubMed Europe PMC Scholia
- Sugasawa K, Okuda Y, Saijo M, Nishi R, Matsuda N, Chu G, Mori T, Iwai S, Tanaka K, Tanaka K, Hanaoka F.; ''UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex.''; PubMed Europe PMC Scholia
- Coin F, Oksenych V, Egly JM.; ''Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair.''; PubMed Europe PMC Scholia
- Oh KS, Imoto K, Emmert S, Tamura D, DiGiovanna JJ, Kraemer KH.; ''Nucleotide excision repair proteins rapidly accumulate but fail to persist in human XP-E (DDB2 mutant) cells.''; PubMed Europe PMC Scholia
- Kuraoka I, Ito S, Wada T, Hayashida M, Lee L, Saijo M, Nakatsu Y, Matsumoto M, Matsunaga T, Handa H, Qin J, Nakatani Y, Tanaka K.; ''Isolation of XAB2 complex involved in pre-mRNA splicing, transcription, and transcription-coupled repair.''; PubMed Europe PMC Scholia
- van Cuijk L, van Belle GJ, van Belle GJ, Turkyilmaz Y, Poulsen SL, Janssens RC, Theil AF, Sabatella M, Lans H, Mailand N, Houtsmuller AB, Vermeulen W, Marteijn JA.; ''SUMO and ubiquitin-dependent XPC exchange drives nucleotide excision repair.''; PubMed Europe PMC Scholia
- Su HL, Li SS.; ''Molecular features of human ubiquitin-like SUMO genes and their encoded proteins.''; PubMed Europe PMC Scholia
- Morris DP, Michelotti GA, Schwinn DA.; ''Evidence that phosphorylation of the RNA polymerase II carboxyl-terminal repeats is similar in yeast and humans.''; PubMed Europe PMC Scholia
- Lindahl T, Wood RD.; ''Quality control by DNA repair.''; PubMed Europe PMC Scholia
- Araújo SJ, Wood RD.; ''Protein complexes in nucleotide excision repair.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC:Incised DNA without lesion | Complex | R-HSA-5690478 (Reactome)  | |
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC:SSB-dsDNA | Complex | R-HSA-5690470 (Reactome) | |
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | Complex | R-HSA-6790530 (Reactome) | |
| 5'-incised damaged DNA:trimmed nascent mRNA | R-NUL-6782202 (Reactome) | ||
| ACTB(1-375) | Protein | P60709 (Uniprot-TrEMBL) | |
| ACTL6A | Protein | O96019 (Uniprot-TrEMBL) | |
| ACTR5 | Protein | Q9H9F9 (Uniprot-TrEMBL) | |
| ACTR8 | Protein | Q9H981 (Uniprot-TrEMBL) | |
| ADP | Metabolite | CHEBI:16761 (ChEBI) | |
| AQR | Protein | O60306 (Uniprot-TrEMBL) | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| CAK | Complex | R-HSA-69221 (Reactome) | |
| CCNH | Protein | P51946 (Uniprot-TrEMBL) | |
| CDK7 | Protein | P50613 (Uniprot-TrEMBL) | |
| CETN2 | Protein | P41208 (Uniprot-TrEMBL) | |
| CETN2 | Protein | P41208 (Uniprot-TrEMBL) | |
| CHD1L | Protein | Q86WJ1 (Uniprot-TrEMBL) | |
| CHD1L | Protein | Q86WJ1 (Uniprot-TrEMBL) | |
| COP9 signalosome | Complex | R-HSA-5697024 (Reactome) | |
| COPS2 | Protein | P61201 (Uniprot-TrEMBL) | |
| COPS3 | Protein | Q9UNS2 (Uniprot-TrEMBL) | |
| COPS4 | Protein | Q9BT78 (Uniprot-TrEMBL) | |
| COPS5 | Protein | Q92905 (Uniprot-TrEMBL) | |
| COPS6 | Protein | Q7L5N1 (Uniprot-TrEMBL) | |
| COPS7A | Protein | Q9UBW8 (Uniprot-TrEMBL) | |
| COPS7B | Protein | Q9H9Q2 (Uniprot-TrEMBL) | |
| COPS8 | Protein | Q99627 (Uniprot-TrEMBL) | |
| CUL4A | Protein | Q13619 (Uniprot-TrEMBL) | |
| CUL4B | Protein | Q13620 (Uniprot-TrEMBL) | |
| DDB1 | Protein | Q16531 (Uniprot-TrEMBL) | |
| DDB2 | Protein | Q92466 (Uniprot-TrEMBL) | |
| Damaged
dsDNA with open transcription bubble:Hyperphosphorylated RNA Pol II:TFIIH | Complex | R-HSA-6781821 (Reactome) | |
| Damaged dsDNA with open transcription bubble | R-NUL-6781820 (Reactome) | ||
| Distorted dsDNA | R-NUL-5688114 (Reactome) | ||
| Distorted dsDNA | R-NUL-5688114 (Reactome) | ||
| ELL | Protein | P55199 (Uniprot-TrEMBL) | |
| EP300 | Protein | Q09472 (Uniprot-TrEMBL) | |
| EP300 | Protein | Q09472 (Uniprot-TrEMBL) | |
| ERCC1 | Protein | P07992 (Uniprot-TrEMBL) | |
| ERCC1:ERCC4 | Complex | R-HSA-109943 (Reactome) | |
| ERCC1 | Protein | P07992 (Uniprot-TrEMBL) | |
| ERCC2 | Protein | P18074 (Uniprot-TrEMBL) | |
| ERCC3 | Protein | P19447 (Uniprot-TrEMBL) | |
| ERCC4 | Protein | Q92889 (Uniprot-TrEMBL) | |
| ERCC4 | Protein | Q92889 (Uniprot-TrEMBL) | |
| ERCC5 | Protein | P28715 (Uniprot-TrEMBL) | |
| ERCC5 | Protein | P28715 (Uniprot-TrEMBL) | |
| ERCC6 | Protein | Q03468 (Uniprot-TrEMBL) | |
| ERCC6 | Protein | Q03468 (Uniprot-TrEMBL) | |
| ERCC8 | Protein | Q13216 (Uniprot-TrEMBL) | |
| ERCC8:DDB1:CUL4:RBX1:COP9 Signalosome | Complex | R-HSA-6781842 (Reactome) | |
| ERCC8:DDB1:CUL4:RBX1 | Complex | R-HSA-6781841 (Reactome) | |
| GG-NER
incision complex:5'-incised damaged DNA:(PCNA:POLD,POLE),(MonoUb:K164-PCNA:POLK):RPA:RFC | Complex | R-HSA-5690214 (Reactome) | |
| GG-NER incision
complex:5'-incised damaged DNA | Complex | R-HSA-5691059 (Reactome) | |
| GG-NER incision
complex:Open bubble dsDNA | Complex | R-HSA-5691046 (Reactome) | |
| GG-NER pre-incision
complex:Open bubble-dsDNA | Complex | R-HSA-5691043 (Reactome) | |
| GPS1 | Protein | Q13098 (Uniprot-TrEMBL) | |
| GTF2H1 | Protein | P32780 (Uniprot-TrEMBL) | |
| GTF2H2 | Protein | Q13888 (Uniprot-TrEMBL) | |
| GTF2H3 | Protein | Q13889 (Uniprot-TrEMBL) | |
| GTF2H4 | Protein | Q92759 (Uniprot-TrEMBL) | |
| GTF2H5 | Protein | Q6ZYL4 (Uniprot-TrEMBL) | |
| H2O | Metabolite | CHEBI:15377 (ChEBI) | |
| HMGN1 | Protein | P05114 (Uniprot-TrEMBL) | |
| HMGN1 | Protein | P05114 (Uniprot-TrEMBL) | |
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:ERCC6:ERCC8:DDB1:CUL4:RBX1 | Complex | R-HSA-6781839 (Reactome) | |
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:ERCC6 | Complex | R-HSA-6781837 (Reactome) | |
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH | Complex | R-HSA-6781822 (Reactome) | |
| INO80 | Protein | Q9ULG1 (Uniprot-TrEMBL) | |
| INO80 complex | Complex | R-HSA-5689568 (Reactome) | |
| INO80B | Protein | Q9C086 (Uniprot-TrEMBL) | |
| INO80C | Protein | Q6PI98 (Uniprot-TrEMBL) | |
| INO80D | Protein | Q53TQ3 (Uniprot-TrEMBL) | |
| INO80E | Protein | Q8NBZ0 (Uniprot-TrEMBL) | |
| ISY1 | Protein | Q9ULR0 (Uniprot-TrEMBL) | |
| K63polyUb-C87-UBE2N | Protein | P61088 (Uniprot-TrEMBL) | |
| K63polyUb:C87-UBE2N:UBE2V2 | Complex | R-HSA-6790510 (Reactome) | |
| LIG1 | Protein | P18858 (Uniprot-TrEMBL) | |
| LIG1,LIG3:XRCC1 | Complex | R-HSA-5690475 (Reactome) | |
| LIG3 | Protein | P49916 (Uniprot-TrEMBL) | |
| MCRS1 | Protein | Q96EZ8 (Uniprot-TrEMBL) | |
| MNAT1 | Protein | P51948 (Uniprot-TrEMBL) | |
| MonoUb-K164-PCNA | Protein | P12004 (Uniprot-TrEMBL) | |
| NAD+ | Metabolite | CHEBI:15846 (ChEBI) | |
| NAM | Metabolite | CHEBI:17154 (ChEBI) | |
| NFRKB | Protein | Q6P4R8 (Uniprot-TrEMBL) | |
| Open bubble-dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1, PAR-PARP2:CHD1L | Complex | R-HSA-6790517 (Reactome) | |
| Open bubble damaged DNA template:trimmed nascent mRNA | R-NUL-6782110 (Reactome) | ||
| PAR-DDB2 | Protein | Q92466 (Uniprot-TrEMBL) | |
| PAR-PARP1 | Protein | P09874 (Uniprot-TrEMBL) | |
| PAR-PARP1,PAR-PARP2 dimers | Complex | R-HSA-5651709 (Reactome) | |
| PAR-PARP2 | Protein | Q9UGN5 (Uniprot-TrEMBL) | |
| PAR-UV-DDB | Complex | R-HSA-5696649 (Reactome) | |
| PARP1 | Protein | P09874 (Uniprot-TrEMBL) | |
| PARP1,PARP2 dimers | Complex | R-HSA-5649884 (Reactome) | |
| PARP2 | Protein | Q9UGN5 (Uniprot-TrEMBL) | |
| PCNA homotrimer,MonoUb:K164-PCNA homotrimer | Complex | R-HSA-6790532 (Reactome) | |
| PCNA | Protein | P12004 (Uniprot-TrEMBL) | |
| PIAS1 | Protein | O75925 (Uniprot-TrEMBL) | |
| PIAS1,3 | Complex | R-HSA-6790455 (Reactome) | |
| PIAS3 | Protein | Q9Y6X2 (Uniprot-TrEMBL) | |
| POLD,POLE | R-HSA-5651800 (Reactome) | ||
| POLD,POLE,POLK | Complex | R-HSA-6790535 (Reactome) | |
| POLD1 | Protein | P28340 (Uniprot-TrEMBL) | |
| POLD2 | Protein | P49005 (Uniprot-TrEMBL) | |
| POLD3 | Protein | Q15054 (Uniprot-TrEMBL) | |
| POLD4 | Protein | Q9HCU8 (Uniprot-TrEMBL) | |
| POLE | Protein | Q07864 (Uniprot-TrEMBL) | |
| POLE2 | Protein | P56282 (Uniprot-TrEMBL) | |
| POLK | Protein | Q9UBT6 (Uniprot-TrEMBL) | |
| POLR2A | Protein | P24928 (Uniprot-TrEMBL) | |
| POLR2B | Protein | P30876 (Uniprot-TrEMBL) | |
| POLR2C | Protein | P19387 (Uniprot-TrEMBL) | |
| POLR2D | Protein | O15514 (Uniprot-TrEMBL) | |
| POLR2E | Protein | P19388 (Uniprot-TrEMBL) | |
| POLR2F | Protein | P61218 (Uniprot-TrEMBL) | |
| POLR2G | Protein | P62487 (Uniprot-TrEMBL) | |
| POLR2H | Protein | P52434 (Uniprot-TrEMBL) | |
| POLR2I | Protein | P36954 (Uniprot-TrEMBL) | |
| POLR2J | Protein | P52435 (Uniprot-TrEMBL) | |
| POLR2K | Protein | P53803 (Uniprot-TrEMBL) | |
| POLR2L | Protein | P62875 (Uniprot-TrEMBL) | |
| PPIE | Protein | Q9UNP9 (Uniprot-TrEMBL) | |
| PPi | Metabolite | CHEBI:29888 (ChEBI) | |
| PRPF19 | Protein | Q9UMS4 (Uniprot-TrEMBL) | |
| Pi | Metabolite | CHEBI:18367 (ChEBI) | |
| RAD23A | Protein | P54725 (Uniprot-TrEMBL) | |
| RAD23B | Protein | P54727 (Uniprot-TrEMBL) | |
| RAD23 | Complex | R-HSA-5688130 (Reactome) | |
| RBX1 | Protein | P62877 (Uniprot-TrEMBL) | |
| RFC Heteropentamer | Complex | R-HSA-68436 (Reactome) | |
| RFC1 | Protein | P35251 (Uniprot-TrEMBL) | |
| RFC2 | Protein | P35250 (Uniprot-TrEMBL) | |
| RFC3 | Protein | P40938 (Uniprot-TrEMBL) | |
| RFC4 | Protein | P35249 (Uniprot-TrEMBL) | |
| RFC5 | Protein | P40937 (Uniprot-TrEMBL) | |
| RNA
Polymerase II holoenzyme complex (hyperphosphorylated) | Complex | R-HSA-109909 (Reactome) | |
| RNA Polymerase II
holoenzyme complex (unphosphorylated) | Complex | R-HSA-113401 (Reactome) | |
| RNF111 | Protein | Q6ZNA4 (Uniprot-TrEMBL) | |
| RPA heterotrimer | Complex | R-HSA-68462 (Reactome) | |
| RPA1 | Protein | P27694 (Uniprot-TrEMBL) | |
| RPA2 | Protein | P15927 (Uniprot-TrEMBL) | |
| RPA3 | Protein | P35244 (Uniprot-TrEMBL) | |
| RPS27A(1-76) | Protein | P62979 (Uniprot-TrEMBL) | |
| RUVBL1 | Protein | Q9Y265 (Uniprot-TrEMBL) | |
| SSB-dsDNA | R-HSA-110340 (Reactome) | ||
| SSB-dsDNA:trimmed nascent mRNA | R-NUL-6782212 (Reactome) | ||
| SUMO1 | Protein | P63165 (Uniprot-TrEMBL) | |
| SUMO1,2,3:UBE2I | Complex | R-HSA-6790471 (Reactome) | |
| SUMO1-C93-UBE2I | Protein | P63279 (Uniprot-TrEMBL) | |
| SUMO2 | Protein | P61956 (Uniprot-TrEMBL) | |
| SUMO2-C93-UBE2I | Protein | P63279 (Uniprot-TrEMBL) | |
| SUMO3 | Protein | P55854 (Uniprot-TrEMBL) | |
| SUMO3-C93-UBE2I | Protein | P63279 (Uniprot-TrEMBL) | |
| TC-NER
incision complex: 5'-incised damaged DNA:trimmed nascent mRNA:(PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | Complex | R-HSA-6782219 (Reactome) | |
| TC-NER
post-incision complex:SSB-dsDNA:trimmed nascent mRNA: (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | Complex | R-HSA-6782220 (Reactome) | |
| TC-NER
post-incision complex:incised DNA without lesion:trimmed nascent mRNA:PCNA:(PCNA:POLD,POLE),(MonoUb:K164-PCNA:POLK):RPA:RFC | Complex | R-HSA-6782222 (Reactome) | |
| TC-NER
pre-incision complex:Open bubble damaged DNA template:RPA:ERCC5:trimmed nascent mRNA | Complex | R-HSA-6782134 (Reactome) | |
| TC-NER incision
complex:5'-incised damaged DNA:trimmed nascent mRNA | Complex | R-HSA-6782205 (Reactome) | |
| TC-NER incision complex | Complex | R-HSA-6782142 (Reactome) | |
| TC-NER post-incision
complex:dsDNA with transcription bubble | Complex | R-HSA-6782230 (Reactome) | |
| TC-NER pre-incision
complex:Open bubble damaged DNA template:trimmed nascent mRNA | Complex | R-HSA-6782111 (Reactome) | |
| TC-NER pre-incision complex | Complex | R-HSA-6782066 (Reactome) | |
| TCEA1 | Protein | P23193 (Uniprot-TrEMBL) | |
| TCEA1 | Protein | P23193 (Uniprot-TrEMBL) | |
| TFIIH Core | Complex | R-HSA-5689624 (Reactome) | |
| TFIIH | Complex | R-HSA-109634 (Reactome) | |
| TFPT | Protein | P0C1Z6 (Uniprot-TrEMBL) | |
| UBA52(1-76) | Protein | P62987 (Uniprot-TrEMBL) | |
| UBB(1-76) | Protein | P0CG47 (Uniprot-TrEMBL) | |
| UBB(153-228) | Protein | P0CG47 (Uniprot-TrEMBL) | |
| UBB(77-152) | Protein | P0CG47 (Uniprot-TrEMBL) | |
| UBC(1-76) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(153-228) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(229-304) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(305-380) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(381-456) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(457-532) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(533-608) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(609-684) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(77-152) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBE2I-G92-SUMO3 | Protein | P55854 (Uniprot-TrEMBL) | |
| UBE2I-G93-SUMO2 | Protein | P61956 (Uniprot-TrEMBL) | |
| UBE2I-G97-SUMO1 | Protein | P63165 (Uniprot-TrEMBL) | |
| UBE2I | Protein | P63279 (Uniprot-TrEMBL) | |
| UBE2N | Protein | P61088 (Uniprot-TrEMBL) | |
| UBE2N:UBE2V2 | Complex | R-HSA-5682542 (Reactome) | |
| UBE2V2 | Protein | Q15819 (Uniprot-TrEMBL) | |
| USP45 | Protein | Q70EL2 (Uniprot-TrEMBL) | |
| USP7 | Protein | Q93009 (Uniprot-TrEMBL) | |
| UV-DDB:COP9 Signalosome | Complex | R-HSA-5697031 (Reactome) | |
| UVSSA | Protein | Q2YD98 (Uniprot-TrEMBL) | |
| UVSSA:USP7 | Complex | R-HSA-6781845 (Reactome) | |
| Ub,SUMO,K63polyUb-XPC | Protein | Q01831 (Uniprot-TrEMBL) | |
| Ub,SUMO,K63polyUb:XPC:RAD23:CETN2 | Complex | R-HSA-6790519 (Reactome) | |
| Ub,SUMO-XPC | Protein | Q01831 (Uniprot-TrEMBL) | |
| Ub,SUMO:XPC:RAD23:CETN2:Open bubble-dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1, PAR-PARP2:CHD1L | Complex | R-HSA-6790468 (Reactome) | |
| Ub,p-S2,S5-POLR2A | Protein | P24928 (Uniprot-TrEMBL) | |
| Ub-139-UBB(77-152) | Protein | P0CG47 (Uniprot-TrEMBL) | |
| Ub-139-UBC(77-152) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-215-UBB(153-228) | Protein | P0CG47 (Uniprot-TrEMBL) | |
| Ub-215-UBC(153-228) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-291-UBC(229-304) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-367-UBC(305-380) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-443-UBC(381-456) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-519-UBC(457-532) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-595-UBC(533-608) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-63-RPS27A(1-76) | Protein | P62979 (Uniprot-TrEMBL) | |
| Ub-63-UBA52(1-76) | Protein | P62987 (Uniprot-TrEMBL) | |
| Ub-63-UBB(1-76) | Protein | P0CG47 (Uniprot-TrEMBL) | |
| Ub-63-UBC(1-76) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-671-UBC(609-684) | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-ERCC1 | Protein | P07992 (Uniprot-TrEMBL) | |
| Ub-ERCC6 | Protein | Q03468 (Uniprot-TrEMBL) | |
| Ub-XPC | Protein | Q01831 (Uniprot-TrEMBL) | |
| Ub:ERCC1 | Complex | R-HSA-5696466 (Reactome) | |
| Ub:ERCC6 | Complex | R-HSA-6781849 (Reactome) | |
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:PAR-PARP1,PAR-PARP2 | Complex | R-HSA-5696681 (Reactome) | |
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2:CHD1L | Complex | R-HSA-5696652 (Reactome) | |
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2 | Complex | R-HSA-5689300 (Reactome) | |
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH:PAR-PARP1,PAR-PARP2 | Complex | R-HSA-5689862 (Reactome) | |
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB:PARP1,PARP2 | Complex | R-HSA-5696660 (Reactome) | |
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB | Complex | R-HSA-6782948 (Reactome) | |
| Ub:XPC:RAD23:CETN2:Open bubble-dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2:CHD1L | Complex | R-HSA-5691018 (Reactome) | |
| Ubiquitinated,hyperphosphorylated RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:Ub:ERCC6:ERCC8:DDB1:CUL4:RBX1:UVSSA:USP7:XAB2 complex:XPA:TCEA1:HMGN1:EP300 | Complex | R-HSA-6782063 (Reactome) | |
| Ubiquitinated,hyperphosphorylated RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:Ub:ERCC6:ERCC8:DDB1:CUL4:RBX1 | Complex | R-HSA-6781866 (Reactome) | |
| XAB2 | Protein | Q9HCS7 (Uniprot-TrEMBL) | |
| XAB2 complex | Complex | R-HSA-6781957 (Reactome) | |
| XPA | Protein | P23025 (Uniprot-TrEMBL) | |
| XPA | Protein | P23025 (Uniprot-TrEMBL) | |
| XPC | Protein | Q01831 (Uniprot-TrEMBL) | |
| XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB | Complex | R-HSA-5691012 (Reactome) | |
| XPC:RAD23:CETN2 | Complex | R-HSA-5691010 (Reactome) | |
| XPC | Protein | Q01831 (Uniprot-TrEMBL) | |
| XRCC1 | Protein | P18887 (Uniprot-TrEMBL) | |
| YY1 | Protein | P25490 (Uniprot-TrEMBL) | |
| ZNF830 | Protein | Q96NB3 (Uniprot-TrEMBL) | |
| dNTP | Metabolite | CHEBI:16516 (ChEBI) | |
| damaged DNA substrate:nascent mRNA hybrid | R-NUL-110291 (Reactome) | ||
| damaged DNA with 5' incision | R-NUL-5691056 (Reactome) | ||
| damaged DNA with open bubble structure | R-NUL-109944 (Reactome) | ||
| dsDNA with transcription bubble | R-NUL-6782229 (Reactome) | ||
| dsDNA | R-HSA-5649637 (Reactome) | ||
| excised DNA fragment with lesion | R-NUL-109960 (Reactome) | ||
| incised DNA without lesion | R-NUL-109961 (Reactome) | ||
| incised DNA without lesion:trimmed nascent mRNA | R-NUL-6782213 (Reactome) | ||
| mRNA | R-HSA-6782236 (Reactome) | ||
| p-S2,S5-POLR2A | Protein | P24928 (Uniprot-TrEMBL) | |
| ribonucleoside triphosphate | Metabolite | CHEBI:17972 (ChEBI) | |
| ubiquitin | Complex | R-HSA-68524 (Reactome) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC:Incised DNA without lesion | Arrow | R-HSA-5690988 (Reactome) | ||
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC:Incised DNA without lesion | R-HSA-5691001 (Reactome) | |||
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC:Incised DNA without lesion | mim-catalysis | R-HSA-5691001 (Reactome) | ||
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC:SSB-dsDNA | Arrow | R-HSA-5691001 (Reactome) | ||
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC:SSB-dsDNA | R-HSA-5690997 (Reactome) | |||
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | Arrow | R-HSA-5690997 (Reactome) | ||
| (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | Arrow | R-HSA-6782227 (Reactome) | ||
| ADP | Arrow | R-HSA-5690996 (Reactome) | ||
| ADP | Arrow | R-HSA-6782131 (Reactome) | ||
| ATP | R-HSA-5690996 (Reactome) | |||
| ATP | R-HSA-6782131 (Reactome) | |||
| CAK | Arrow | R-HSA-5689861 (Reactome) | ||
| CETN2 | R-HSA-5691004 (Reactome) | |||
| CHD1L | Arrow | R-HSA-5690988 (Reactome) | ||
| CHD1L | R-HSA-5696670 (Reactome) | |||
| COP9 signalosome | Arrow | R-HSA-5691006 (Reactome) | ||
| COP9 signalosome | Arrow | R-HSA-6781833 (Reactome) | ||
| Damaged
dsDNA with open transcription bubble:Hyperphosphorylated RNA Pol II:TFIIH | Arrow | R-HSA-6781818 (Reactome) | ||
| Damaged
dsDNA with open transcription bubble:Hyperphosphorylated RNA Pol II:TFIIH | R-HSA-6781824 (Reactome) | |||
| Damaged
dsDNA with open transcription bubble:Hyperphosphorylated RNA Pol II:TFIIH | mim-catalysis | R-HSA-6781824 (Reactome) | ||
| Distorted dsDNA | R-HSA-5691006 (Reactome) | |||
| Distorted dsDNA | R-HSA-6781818 (Reactome) | |||
| ELL | Arrow | R-HSA-6782234 (Reactome) | ||
| EP300 | Arrow | R-HSA-6782234 (Reactome) | ||
| EP300 | R-HSA-6782004 (Reactome) | |||
| ERCC1:ERCC4 | Arrow | R-HSA-109955 (Reactome) | ||
| ERCC1:ERCC4 | Arrow | R-HSA-5690988 (Reactome) | ||
| ERCC1:ERCC4 | Arrow | R-HSA-6782224 (Reactome) | ||
| ERCC1:ERCC4 | R-HSA-5690991 (Reactome) | |||
| ERCC1:ERCC4 | R-HSA-6782141 (Reactome) | |||
| ERCC1 | Arrow | R-HSA-5696465 (Reactome) | ||
| ERCC1 | R-HSA-109955 (Reactome) | |||
| ERCC4 | R-HSA-109955 (Reactome) | |||
| ERCC5 | Arrow | R-HSA-5690988 (Reactome) | ||
| ERCC5 | Arrow | R-HSA-6782224 (Reactome) | ||
| ERCC5 | R-HSA-5689317 (Reactome) | |||
| ERCC5 | R-HSA-6782138 (Reactome) | |||
| ERCC6 | R-HSA-6781840 (Reactome) | |||
| ERCC8:DDB1:CUL4:RBX1:COP9 Signalosome | R-HSA-6781833 (Reactome) | |||
| ERCC8:DDB1:CUL4:RBX1 | Arrow | R-HSA-6782234 (Reactome) | ||
| GG-NER
incision complex:5'-incised damaged DNA:(PCNA:POLD,POLE),(MonoUb:K164-PCNA:POLK):RPA:RFC | Arrow | R-HSA-5690213 (Reactome) | ||
| GG-NER
incision complex:5'-incised damaged DNA:(PCNA:POLD,POLE),(MonoUb:K164-PCNA:POLK):RPA:RFC | R-HSA-5690988 (Reactome) | |||
| GG-NER
incision complex:5'-incised damaged DNA:(PCNA:POLD,POLE),(MonoUb:K164-PCNA:POLK):RPA:RFC | mim-catalysis | R-HSA-5690988 (Reactome) | ||
| GG-NER incision
complex:5'-incised damaged DNA | Arrow | R-HSA-5690990 (Reactome) | ||
| GG-NER incision
complex:5'-incised damaged DNA | R-HSA-5690213 (Reactome) | |||
| GG-NER incision
complex:Open bubble dsDNA | Arrow | R-HSA-5690991 (Reactome) | ||
| GG-NER incision
complex:Open bubble dsDNA | R-HSA-5690990 (Reactome) | |||
| GG-NER incision
complex:Open bubble dsDNA | mim-catalysis | R-HSA-5690990 (Reactome) | ||
| GG-NER pre-incision
complex:Open bubble-dsDNA | Arrow | R-HSA-5689317 (Reactome) | ||
| GG-NER pre-incision
complex:Open bubble-dsDNA | R-HSA-5690991 (Reactome) | |||
| H2O | R-HSA-5696465 (Reactome) | |||
| H2O | R-HSA-6782069 (Reactome) | |||
| HMGN1 | Arrow | R-HSA-6782234 (Reactome) | ||
| HMGN1 | R-HSA-6782004 (Reactome) | |||
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:ERCC6:ERCC8:DDB1:CUL4:RBX1 | Arrow | R-HSA-6781833 (Reactome) | ||
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:ERCC6:ERCC8:DDB1:CUL4:RBX1 | R-HSA-6781867 (Reactome) | |||
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:ERCC6:ERCC8:DDB1:CUL4:RBX1 | mim-catalysis | R-HSA-6781867 (Reactome) | ||
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:ERCC6 | Arrow | R-HSA-6781840 (Reactome) | ||
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:ERCC6 | R-HSA-6781833 (Reactome) | |||
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH | Arrow | R-HSA-6781824 (Reactome) | ||
| Hyperphosphorylated
RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH | R-HSA-6781840 (Reactome) | |||
| INO80 complex | Arrow | R-HSA-5691006 (Reactome) | ||
| K63polyUb:C87-UBE2N:UBE2V2 | R-HSA-6790487 (Reactome) | |||
| LIG1,LIG3:XRCC1 | mim-catalysis | R-HSA-5690997 (Reactome) | ||
| LIG1,LIG3:XRCC1 | mim-catalysis | R-HSA-6782227 (Reactome) | ||
| NAD+ | R-HSA-5696655 (Reactome) | |||
| NAM | Arrow | R-HSA-5696655 (Reactome) | ||
| Open bubble-dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1, PAR-PARP2:CHD1L | Arrow | R-HSA-6790487 (Reactome) | ||
| Open bubble-dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1, PAR-PARP2:CHD1L | R-HSA-5689317 (Reactome) | |||
| PAR-PARP1,PAR-PARP2 dimers | Arrow | R-HSA-5690988 (Reactome) | ||
| PAR-UV-DDB | Arrow | R-HSA-5690988 (Reactome) | ||
| PARP1,PARP2 dimers | R-HSA-5696664 (Reactome) | |||
| PCNA homotrimer,MonoUb:K164-PCNA homotrimer | R-HSA-5690213 (Reactome) | |||
| PCNA homotrimer,MonoUb:K164-PCNA homotrimer | R-HSA-6782211 (Reactome) | |||
| PIAS1,3 | mim-catalysis | R-HSA-6790454 (Reactome) | ||
| POLD,POLE,POLK | R-HSA-5690213 (Reactome) | |||
| POLD,POLE,POLK | R-HSA-6782211 (Reactome) | |||
| PPi | Arrow | R-HSA-5691001 (Reactome) | ||
| PPi | Arrow | R-HSA-6781824 (Reactome) | ||
| PPi | Arrow | R-HSA-6782208 (Reactome) | ||
| Pi | Arrow | R-HSA-5690996 (Reactome) | ||
| Pi | Arrow | R-HSA-6782131 (Reactome) | ||
| R-HSA-109955 (Reactome) | ERCC1 binds ERCC4 (XPF) to form a heterodimeric ERCC1:ERCC4 (ERCC1:XPF) complex with a DNA endonuclease activity, where ERCC4 is the catalytic subunit. Suitable substrates for the ERCC1:ERCC4 endonuclease are single strand DNA (ssDNA) and ssDNA region of a duplex DNA with an open bubble structure (Park et al. 1995). | |||
| R-HSA-5689317 (Reactome) | Once an open bubble structure is generated in damaged dsDNA through a DNA helicase activity of the TFIIH complex, the RPA heterotrimer composed of RPA1, RPA2 and RPA3, coats the undamaged single strand DNA (ssDNA) (de Laat et al. 1998), thereby protecting it from incision and enabling the correct positioning of the NER endonucleases. The interaction of RPA with XPA facilitates RPA recruitment to the global genome nucleotide excision repair (GG-NER) site (He et al. 1995, Ikegami et al. 1998). A DNA endonuclease ERCC5 (XPG) is recruited to the GG-NER site, 3' to the DNA damage, through its interaction with the TFIIH complex (Dunand-Sauthier et al. 2005, Zotter et al. 2006, Ito et al. 2007) and the RPA heterotrimer (de Laat et al. 1998). | |||
| R-HSA-5689861 (Reactome) | XPA binds the DNA damage site through interaction with the TFIIH complex subunit GTF2H5 (TTDA) (Ziani et al. 2014), and also interacts with the DDB2 subunit of the UV-DDB complex (Wakasugi et al. 2001, Wakasugi et al. 2009, Takedachi et al. 2010). PARylated PARP1 (or possibly PARP2) (King et al. 2012) facilitates XPA association with chromatin. Binding of XPA is accompanied by the release of the CAK subcomplex from the TFIIH complex (Coin et al. 2008). | |||
| R-HSA-5690213 (Reactome) | The DNA repair synthesis complex, consisting of PCNA, RFC, RPA and polymerase delta (POLD) or epsilon (POLE) complexes, or DNA translesion synthesis polymerase kappa (POLK) (Ogi et al. 2010), is formed at the nucleotide excision repair (NER) site following the incision of the damaged DNA strand 5' to the lesion by the ERCC1:ERCC4 (ERCC1:XPF) complex. 3' incision by XPG (ERCC5) is not required for the loading of the DNA polymerases and may not be required for the initiation of NER-mediated DNA synthesis (Staresincic et al. 2009). XPG and RPA promote the assembly of the DNA synthesis complex at the NER site (Mocquet et al. 2008). | |||
| R-HSA-5690988 (Reactome) | In global genome nucleotide excision repair (GG-NER), as well as transcription-coupled nucleotide excision repair (TC-NER), the cleavage of the damaged DNA strand 3' to the site of damage is carried out by a DNA endonuclease XPG (ERCC5). While the DNA repair synthesis may be initiated prior to the 3' incision (Staresincic et al. 2009), the components of the incision complex probably dissociate from the NER site shortly after the replicative complex assembly and 3' incision (Overmeer et al. 2011). The exception is the RPA heterotrimer, which is a constituent of the DNA synthesis complex, and also coats the undamaged DNA strand, thereby protecting it from endonucleolytic cleavage. | |||
| R-HSA-5690990 (Reactome) | In global genome nucleotide excision repair (GG-NER), just like in transcription-coupled nucleotide excision repair (TC-NER), the cleavage of the damaged strand of DNA 5' to the site of damage occurs at the junction of single-stranded DNA and double-stranded DNA that is formed when the DNA duplex is unwound. The 5' incision is carried out by the ERCC1:XPF (ERCC1:ERCC4) complex and precedes the 3' incision (Staresincic et al. 2009). | |||
| R-HSA-5690991 (Reactome) | ERCC1:ERCC4 (ERCC1:XPF) DNA endonuclease complex binds 5' to the DNA damage at global genome nucleotide excision repair (GG-NER) sites to form the incision complex. Binding of ERCC5 (XPG) to the NER site precedes the recruitment of ERCC1:ERCC4 (Riedl et al. 2003). ERCC1 directly interacts with XPA, and this interaction is necessary for the loading of ERCC1:ERCC4 to the open bubble structure in damaged dsDNA and the progression of GG-NER (Tsodikov et al. 2007, Orelli et al. 2010). | |||
| R-HSA-5690996 (Reactome) | Two DNA helicases XPB (ERCC3) and XPD (ERCC2), which are part of the TFIIH complex, unwind the distorted DNA duplex around the lesion to form an open bubble structure that exposes the damaged site. The helicase activity of the TFIIH complex is stimulated by the presence of XPA and the XPC:RAD23:CETN2 complex (Winkler et al. 2001). The 5'->3' directed helicase activity of ERCC2 (Kuper et al. 2012) is crucial for unwinding of the distorted dsDNA during nucleotide excision repair (NER) (Coin et al. 2007). The 3'->5' directed DNA helicase ERCC3 contributes to dsDNA unwinding during NER through ATP hydrolysis (Coin et al. 2007). In addition to DNA unwinding, ERCC2 and ERCC3 verify the presence of DNA damage (Oksenych et al. 2009, Mathieu et al. 2010, Mathieu et al. 2013). Verification of DNA damage also involves XPA (Camenisch et al. 2006). The binding site of XPC determines which DNA strand is selected by ERCC2 to verify the presence of lesions (Sugasawa et al. 2009). | |||
| R-HSA-5690997 (Reactome) | The nucleotide excision repair (NER) is completed when the newly synthesized fragment is ligated to the incised DNA strand, thus closing the single stranded nick (SSB). Two DNA ligases, LIG1 and LIG3 (as part of the LIG3:XRCC1 complex) can perform the ligation in global genome NER (GG-NER), as well as in transcription-coupled NER (TC-NER). The choice of NER DNA ligase depends on the DNA polymerase involved in the repair synthesis and on the stage of the cell cycle (Moser et al. 2007). | |||
| R-HSA-5691000 (Reactome) | Transcription factor II H (TFIIH) complex is recruited to DNA damage sites after the damage is recognized by the XPC:RAD23:CETN2 complex and the UV-DDB complex (DDB1:DDB2) (Volker et al. 2001, Araujo and Wood 1999). TFIIH consists of ten subunits organized into a ring-like structure (Schultz et al. 2000). The TFIIH core, also forming a ring-like structure, includes a DNA helicase ERCC3 (XPB), GTF2H1 (BTF2-p62), GTF2H2 (BTF2-p44), GTF2H3 (BTF2-p34) and GTF2H4 (BTF2-p52). GTF2H4 directly interacts with ERCC3 and anchors it to the TFIIH complex (Jawhari et al. 2002). Another DNA helicase, ERCC2 (XPD) is anchored to the TFIIH complex by binding to the GTF2H2 subunit (Coin et al. 1998). The CDK-activating kinase (CAK) complex, consisting of CCNH (cyclin H), CDK7 and MNAT1 (MAT1) is included in the TFIIH complex through an interaction with ERCC2 (Reardon et al. 1996, Rossignol et al. 1997). The tenth subunit, GTF2H5 (TTDA, TFB5, BTF2-p5) is important for the stability of the TFIIH complex (Giglia-Mari et al. 2004). The TFIIH complex binds the DNA damage site after XPC:RAD23:CETN2 complex recognizes the damage (Volker et al. 2001, Riedl et al. 2003), and the ERCC3 and GTF2H1 subunits of TFIIH directly interact with XPC (Yokoi et al. 2003). | |||
| R-HSA-5691001 (Reactome) | In global genome nucleotide excision repair (GG-NER), as well as transcription-coupled nucleotide excision repair (TC-NER), the DNA synthesis complex consisting of PCNA, RPA, RFC and polymerase delta (POLD) or epsilon (POLE) complexes performs DNA repair synthesis after the damaged DNA strand is incised 5' to the lesion by the endonuclease complex ERCC1:ERCC4 (ERCC1:XPF) and 3' to the lesion by the endonuclease XPG (ERCC5). Depending on damage-induced PCNA monoubiquitination, DNA polymerase kappa (POLK) is also involved in gap-filling DNA synthesis during nucleotide excision repair (NER) (Balajee et al. 1998, Staresincic et al. 2009, Ogi et al. 2010, Overmeer et al. 2011). | |||
| R-HSA-5691004 (Reactome) | XPC is mutated in individuals with xeroderma pigmentosum from genetic Complementation Group C (XP-C). It forms a tight complex with RAD23B (HR23B) or, to a lesser extent, RAD23A (HR23A), two human homologs of yeast Rad23 (Masutani et al. 1994, Ng et al. 2003). CETN2 (centrin 2, CEN2) is also part of the XPC complex with RAD23 (Araki et al. 2001, Nishi et al. 2005). | |||
| R-HSA-5691006 (Reactome) | XPC, in complex with RAD23B or RAD23A and CETN2, employs a two-stage process to recognize a distorted DNA helix. In the first stage, XPC rapidly probes dsDNA, which is promoted by a DNA repulsive action of a negatively charged beta-turn extension of XPC, located in the vicinity of the XPC DNA-binding domain. In the second stage, the DNA binding domain, consisting of two beta hairpins, binds non-hydrogen bonded bases in dsDNA (Camenisch et al. 2009). Rad4, the yeast ortholog of XPC, recognizes lesions that thermodynamically disrupt normal Watson-Crick base pairing. Rad4 inserts a beta-hairpin through the DNA duplex, causing damaged base pairs to flip out of the double helix. Rad4 associates with the undamaged strand, whereas the DNA strand that contains damaged nucleotides becomes distorted (Min and Pavletich 2007). Binding of the XPC:RAD23:CETN2 complex to distorted DNA is enhanced in the presence of the DDB1:DDB2 complex, also known as the UV-DDB complex. The UV-DDB complex preferentially binds UV-generated lesions, such as pyrimidine-pyrimidone photodimers (6-4 PPDs) and cyclobutane pyrimidine dimers (CPDs), but also recognizes DNA with apurinic/apyrimidinic (AP) sites, and 2-3 bp mismatches (Fujiwara et al. 1999, Wittschieben et al. 2005). The DDB2 subunit of the UV-DDB complex is a WD40 repeat beta-propeller protein. The beta-propeller domain of DDB2 binds the damaged DNA strand (Scrima et al. 2008). The UV-DDB complex is part of a larger ubiquitin ligase complex that, besides DDB1 and DDB2, also contains CUL4A or CUL4B and RBX1 (Groisman et al. 2003, Sugasawa et al. 2005). In the case of 6-4 PPDs and CPDs, UV-DDB binding to damaged DNA probably precedes the binding of the XPC:RAD23:CETN2 complex. However, in the case of 6-4 PPDs, the XPC:RAD23:CETN2 complex may also recognize damaged DNA in the absence of the UV-DDB complex (Fitch et al. 2003, Moser et al. 2005, Wang et al. 2004), but the UV-DDB complex may be important for retention of DNA repair proteins at the DNA damage site (Oh et al. 2011). The INO80 chromatin remodelling complex positively regulates GG-NER. INO80 and ACTR5 (ARP5) subunits of the INO80 complex are enriched at GG-NER sites, probably via interaction with DDB1. Chromatin relaxation by the INO80 complex at DNA damage site may be necessary for XPC recruitment (Jiang et al. 2010). In yeast, the interaction between INO80 and the orthologs of XPC and RAD23 has been reported and it was suggested that this interaction is important for the restoration of chromatin structure after GG-NER completion (Sarkar et al. 2010). | |||
| R-HSA-5696465 (Reactome) | USP45 ubiquitin protease, mutated in prostate cancer and B-cell lymphoma, deubiquitinates ERCC1. While the mechanism and timing of ERCC1 ubiquitination are not known, deubiquitination of ERCC1 by USP45 enables ERCC1 recruitment to DNA damage sites in nucleotide excision repair (NER) and repair of interstrand cross-links (ICLR) (Perez-Oliva et al. 2015). | |||
| R-HSA-5696655 (Reactome) | PARP1 and/or PARP2 homo- or heterodimers recruited to global genomic nucleotide excision repair (GG-NER) site poly(ADP)ribosylate (PARylate) DDB2 and also progressively autoPARylate. PARylation promotes retention of DDB2 at DNA damage sites (Pines et al. 2012, Robu et al. 2013). | |||
| R-HSA-5696664 (Reactome) | PARP1 (or PARP2) is recruited to global genomic nucleotide excision repair (GG-NER) site through interaction with DDB2 and, probably, distorted single strand DNA (Pines et al. 2012, Robu et al. 2013). | |||
| R-HSA-5696670 (Reactome) | A chromatin remodeling enzyme CHD1L (ALC1) is recruited to DNA damage sites through interaction with PARylated PARP1 (or possibly PARP2) (Ahel et al. 2009) or PARylated DDB2 (Pines et al. 2012). CHD1L catalyzes PARP-stimulated nucleosome sliding and is needed for efficient PARP-dependent DNA repair (Ahel et al. 2009). CHD1L depletion or PARP inhibition impair global genomic nucleotide excision repair (GG-NER) of UV-induced DNA damage (Pines et al. 2012). | |||
| R-HSA-6781818 (Reactome) | Once the transcription is initiated from a DNA template that contains an RNA polymerase II (RNA Pol II) promoter, RNA Pol II synthesizes mRNA in the presence of the elongation complex TFIIH until the damaged DNA base(s) is reached (Brueckner et al. 2007). | |||
| R-HSA-6781824 (Reactome) | An active RNA polymerase II complex (RNA Pol II, POLR2) transcribes a damaged DNA template. Once damaged DNA bases, such as cyclobutane pyrimidine dimers (CPDs), enter the active site of the polymerase, RNA Pol II misincorporates a ribonucleotide into nascent mRNA, which blocks the translocation step and results in polymerase stalling. In the stalled complex, the lesion is inaccessible, while the RNA Pol II conformation is unchanged (Brueckner et al. 2007). | |||
| R-HSA-6781833 (Reactome) | Cockayne syndrome protein A (ERCC8, also known as CSA) is recruited to a stalled RNA polymerase II complex (RNA Pol II) at a site of DNA damage in an ERCC6 (CSB) dependent manner (Fousteri et al. 2006). ERCC8 is part of an ubiquitin ligase complex that, in addition to ERCC8, also contains DDB1, CUL4 (CUL4A or CUL4B) and RBX1 (Groisman et al. 2003). The COP9 signalosome complex prevents the ubiquitin ligase activity of the ERCC8:DDB1:CUL4:RBX1 at the early steps after DNA damage induction (Groisman et al. 2003, Fischer et al. 2011). | |||
| R-HSA-6781840 (Reactome) | Cockayne syndrome protein B (ERCC6, also known as CSB) binds RNA polymerase II complex (RNA Pol II) stalled at a DNA damage site (Fousteri et al. 2006). | |||
| R-HSA-6781867 (Reactome) | The ubiquitin ligase complex ERCC8:DDB1:CUL4:RBX1 may ubiquitinate ERCC6 (CSB) (Groisman et al. 2006) at the later steps of TC-NER and may also be required in the ubiquitination of the RNA Pol II subunit POLR2A in response to damage (Bregman et al. 1996, Lee et al. 2002). Ubiquitination mediated by ERCC8 (CSA) containing ubiquitin ligase complex plays an important role in progression and termination of transcription-coupled nucleotide excision repair (TC-NER), although the mechanistic details are largely unknown. | |||
| R-HSA-6782004 (Reactome) | In addition to ERCC6 (CSB) and the ERCC8 (CSA) ubiquitin ligase complex, several other proteins and protein complexes are loaded onto stalled RNA polymerase II (RNA Pol II) at DNA damage sites to form a pre-incision complex that operates in the transcription-coupled nucleotide excision repair (TC-NER). XPA, which also participates in global genome nucleotide excision repair (GG-NER), is necessary for the progression of TC-NER (Furuta et al. 2002). XPA interacts with the GTF2H5 subunit of the TFIIH complex (Ziani et al. 2014). In GG-NER, XPA loading is accompanied by the release of the CAK subcomplex from TFIIH (Coin et al. 2008), but in TC-NER the CAK complex remains bound to the TC-NER site (Mourgues et al. 2013). XAB2 protein exists in the complex with five other proteins, AQR, PRPF19, ZNF830, ISY1 and PPIE. The XAB2 complex, which is also involved in pre-mRNA splicing, loads onto stalled RNA Pol II site (Kuraoka et al. 2008) through the interaction of XAB2 with RNA Pol II, ERCC6, ERCC8 and XPA (Nakatsu et al. 2000). The AQR (aquarius) subunit of the XAB2 complex is an RNA-DNA helicase that processes R-loops. An R-loop is a structure formed by hybridization of a nascent mRNA with a DNA template. In the absence of AQR, TC-NER machinery processes R-loops into double strand breaks (Sollier et al. 2014). TCEA1 (TFIIS) is a transcription elongation factor that facilitates partial digestion of the 3' protruding end of the nascent transcript by a stalled RNA Pol II, which is generated during the reverse translocation of RNA Pol II from the damage site, and allows the resumption of RNA synthesis once the DNA damage is removed (Donahue et al. 1994). HMGN1, a non-histone high mobility group N nucleosome-binding protein, facilitates TC-NER probably by increasing accessibility of damaged DNA to repair machinery. HMGN1 is recruited at RNA Pol II/TC-NER sites in an ERCC8 (CSA)-dependent manner (Birger et al. 2003, Fousteri et al. 2006). Histone acetyltransferase p300 (EP300) is recruited to stalled RNA Pol II/TC-NER complexes in an ERCC6-dependent manner, and probably acts to facilitate access of repair proteins to damaged DNA via chromatin remodeling (Fousteri et al. 2006). UVSSA protein forms a complex with ubiquitin protease USP7. It is recruited to TC-NER sites via interaction with ubiquitinated RNA Pol II and ERCC6. The UVSSA:USP7 complex stabilizes ERCC6, preventing its proteasome-mediated degradation prior to TC-NER completion, and may de-ubiquitinate RNA Pol II after TC-NER is completed, to allow resumption of RNA synthesis (Nakazawa et al. 2012, Schwertman et al. 2012, Zhang et al. 2012, Fei and Chen 2012). | |||
| R-HSA-6782069 (Reactome) | UVSSA stabilizes ERCC6 (CSB) during transcription-coupled nucleotide excision repair (TC-NER) by targeting ubiquitin protease USP7 to ubiquitinated ERCC6, thus preventing proteasome-mediated degradation of ERCC6. Mutations in UVSSA cause UV-sensitive syndrome (Nakazawa et al. 2012, Schwertman et al. 2012, Zhang et al. 2012, Fei and Chen 2012). | |||
| R-HSA-6782131 (Reactome) | Two DNA helicases XPB (ERCC3) and XPD (ERCC2), which are part of the TFIIH complex, unwind the distorted DNA duplex around the lesion to form an open bubble structure that exposes the damaged site. The 5'->3 directed helicase activity of ERCC2 (Kuper et al. 2012) together with the ATPase activity of the 3'->5' directed DNA helicase ERCC3 contribute to dsDNA unwinding during nucleotide excision repair (NER) (Coin et al. 2007). In transcription-coupled NER (TC-NER), the ATPase activity of TFIIH complex, related to its helicase activity, is in addition necessary for the incision of the damaged DNA strand. While the endonuclease ERCC5 (XPG) can bind stalled RNA polymerase II (RNA Pol II) at a transcription bubble, it cannot perform incision in the absence of the TFIIH ATPase activity (Sarker et al. 2005). The helicase activity of the TFIIH complex may allow backtracking of the RNA Pol II, similar to the UvrD helicase involved in TC-NER in E.coli. Pulling RNA Pol II backwards from the DNA damage site would resolve steric hindrance of the RNA Pol II complex with the TC-NER endonucleases (Epshtein et al. 2014). RNA Pol II backtracking is accompanied by a partial digestion of the nascent 3' protruding mRNA via the 3'->5' directed exonuclease activity of RNA Pol II, which is stimulated by TCEA1 (TFIIS) (Donahue et al. 1994). Partial transcript digestion and RNA Pol II backtracking move the transcription bubble away from the open bubble that contains the DNA damage site (reviewed by Hanawalt and Spivak 2008). | |||
| R-HSA-6782138 (Reactome) | It has been suggested that, similar to the UvrD helicase involved in TC-NER in E.coli, the DNA helicase activity of TFIIH complex may facilitate damage-stalled RNA polymerase II (RNA Pol II) backtracking (Epshtein et al. 2014). RNA Pol II backtracking, together with the cleavage of the 3' protruding end of nascent mRNA, might promote the movement of the transcription bubble away from the transcription-coupled nucleotide excision repair (TC-NER) site, while an open bubble is created (Sarker et al. 2005, Hanawalt and Spivak 2008). Once the open bubble is generated, the RPA heterotrimer composed of RPA1, RPA2 and RPA3 coats the undamaged single strand DNA (ssDNA) (de Laat et al. 1998), thereby protecting it from endonucleases. The interaction of RPA with XPA facilitates RPA recruitment to the nucleotide excision repair (NER) site (He et al. 1995, Ikegami et al. 1998). A DNA endonuclease ERCC5 (XPG) is recruited to the TC-NER site through its interaction with the stalled RNA Pol II (Sarker et al. 2005), the TFIIH complex (Dunand-Sauthier et al. 2005, Zotter et al. 2006, Ito et al. 2007) and the RPA heterotrimer (de Laat et al. 1998). | |||
| R-HSA-6782141 (Reactome) | ERCC1:ERCC4 (ERCC1:XPF) DNA endonuclease complex binds to the pre-incision complex at the transcription-coupled nucleotide excision repair (TC-NER) site to form the incision complex. Binding of ERCC5 (XPG) to the NER site precedes the recruitment of ERCC1:ERCC4 (Riedl et al. 2003). ERCC1 directly interacts with the XPA, and this interaction is necessary for the loading of ERCC1:ERCC4 to the open bubble structure in damaged dsDNA and the progression of TC-NER (Tsodikov et al. 2007, Orelli et al. 2010). | |||
| R-HSA-6782204 (Reactome) | In transcription-coupled nucleotide excision repair (TC-NER), just like in global genome nucleotide excision repair (GG-NER), the cleavage of the damaged strand of DNA 5' to the site of damage occurs at the junction of single-stranded DNA and double-stranded DNA that is formed when the DNA duplex is unwound. The 5' incision is carried out by ERCC1:XPF (ERCC1:ERCC4) complex and precedes the 3' incision by ERCC5 (XPG) (Staresincic et al. 2009). | |||
| R-HSA-6782208 (Reactome) | In transcription-coupled nucleotide excision repair (TC-NER), as well as in global genome nucleotide excision repair (GG-NER), the DNA synthesis complex (NER post-incision complex) consisting of PCNA, RPA, RFC and polymerase delta (POLD) or epsilon (POLE) complexes performs DNA repair synthesis after the damaged DNA strand is incised 5' to the lesion by the endonuclease complex ERCC1:ERCC4 (ERCC1:XPF) and 3' to the lesion by the endonuclease XPG (ERCC5). Depending on damage-induced PCNA monoubiquitination, DNA polymerase kappa (POLK) may also be involved in gap-filling DNA synthesis during nucleotide excision repair (NER) (Balajee et al. 1998, Staresincic et al. 2009, Ogi et al. 2010, Overmeer et al. 2011). | |||
| R-HSA-6782211 (Reactome) | The DNA repair synthesis complex, consisting of PCNA, RFC, RPA and polymerase delta (POLD) or epsilon (POLE) complexes, or polymerase kappa (POLK), is formed at the transcription coupled nucleotide excision repair (TC-NER) site, as well as the global genome nucleotide excision repair (GG-NER) site, following the incision of the damaged DNA strand 5' to the lesion by the ERCC1:ERCC4 (ERCC1:XPF) complex. 3' incision by XPG (ERCC5) is not required for the loading of the DNA polymerases and may not be required for the initiation of NER-mediated DNA synthesis (Staresincic et al. 2009). XPG and RPA promote the assembly of the DNA synthesis complex at the NER site (Mocquet et al. 2008). | |||
| R-HSA-6782224 (Reactome) | In transcription-coupled nucleotide excision repair (TC-NER), as well as in global genome nucleotide excision repair (GG-NER), the cleavage of the damaged DNA strand 3' to the site of damage is carried out by a DNA endonuclease XPG (ERCC5). While the NER-mediated DNA synthesis may be initiated prior to the 3' incision (Staresincic et al. 2009), the components of the incision complex probably dissociate from the NER site shortly after the DNA synthesis complex assembly and 3' incision (Overmeer et al. 2011). The exception is the RPA heterotrimer, which is a constituent of the NER post-incision complex, and also coats the undamaged DNA strand, thereby protecting it from endonucleolytic cleavage. RNA polymerase II-associated factors also remain bound to the TC-NER site. | |||
| R-HSA-6782227 (Reactome) | The nucleotide excision repair (NER) is completed when the newly synthesized fragment is ligated to the incised DNA strand, thus sealing the single stranded nick (SSB). Two DNA ligases, LIG1 and LIG3 (as a part of LIG3:XRCC1 complex) can perform the ligation in transcription-coupled NER (TC-NER), as well as in global genome NER (GG-NER). The choice of NER DNA ligase depends on the DNA polymerase involved in repair synthesis and probably the stage of the cell cycle (Moser et al. 2007). | |||
| R-HSA-6782234 (Reactome) | After DNA repair synthesis is completed at transcription-coupled nucleotide excision repair (TC-NER) sites, transcription resumes. A number of factors have been implicated in this process. ERCC6 (CSB) contains an ubiquitin-binding domain that is indispensable for its function in TC-NER and the restoration of damage-inhibited RNA synthesis (Anindya et al. 2010). The ubiquitin ligase activity of the ERCC8:DDB1:CUL4:RBX1 complex plays an important role in termination of TC-NER, possibly by targeting ERCC6 or its ubiquitinated partner for degradation and promoting dissociation of repair factors from the RNA polymerase II complex (Groisman et al. 2006, Vermeulen and Fousteri 2013). The ubiquitin protease complex composed of UVSSA and USP7 is also implicated in the recovery of RNA synthesis (RRS) (Nakazawa et al. 2012, Scwertman et al. 2012, Zhang et al. 2012, Fei and Chen 2012). ELL protein, recruited to the TFIIH complex, possibly as a component of the little elongation complex, is needed for RRS (Mourgues et al. 2013). Furthermore, histone chaperone FACT promotes accelerated histone exchange at TC-NER sites, allowing efficient progression of TC-NER and restoration of RNA synthesis after the repair of transcription blocking damages is completed (Dinant et al. 2013). | |||
| R-HSA-6782943 (Reactome) | The role of UV-DDB-mediated ubiquitination in global genome nucleotide excision repair (GG-NER) has not been fully elucidated. In the absence of DNA damage, the ubiquitin ligase activity of UV-DDB complex is inhibited by association with the COP9 signalosome (CSN complex), which dissociates from the UV-DDB complex upon binding to damaged DNA (Groisman et al. 2003, Fischer et al. 2011). Ubiquitination of XPC by UV-DDB promotes XPC retention at GG-NER sites, while progressive autoubiquitination of UV-DDB promotes the dissociation of UV-DDB from the DNA and may act as an intracellular signal (Sugasawa et al. 2005). The UV-DDB complex also ubiquitinates histones H2A, H3 and H4, which may trigger chromatin remodeling at DNA damage site and regulate the accessibility of damaged DNA to repair factors (Kapetanaki et al. 2006, Wang et al. 2006). | |||
| R-HSA-6790454 (Reactome) | XPC undergoes SUMOylation following UV irradiation on several consensus SUMOylation sites (van Cuijk et al. 2015). SUMOylation of XPC probably succeeds the UV-DDB mediated ubiquitination of XPC, as the presence of both DDB2 and XPA is required for SUMOylation (Wang et al. 2005), but it has also been reported that SUMOylation of XPC was DDB2-independent (Akita et al. 2015). It is unclear whether XPC is modified by SUMO1 (Wang et al. 2005, Akita et al. 2015) or poly-SUMO2/3 (Poulsen et al. 2013). SUMO conjugases PIAS1 and PIAS3 both interact with XPC and may catalyze XPC SUMOylation (Akita et al. 2015). | |||
| R-HSA-6790487 (Reactome) | SUMOylated XPC is recognized by the SUMO-targeted ubiquitin ligase RNF111 (Arcadia) that, together with the E2 ubiquitin conjugating complex of UBE2N (UBC13) and UBE2V2 (MMS2), generates K63-linked polyubiquitin chains on XPC (Poulsen et al. 2013) to efficiently release XPC from UV lesions (van Cuijk et al. 2015). The release of K63-polyubiquitinated XPC occurs from GG-NER pre-incision complexes that contain TFIIH and XPA and promotes optimal access/binding of ERCC5 (XPG) endonuclease to the pre-incision complex (van Cuijk et al. 2015). Successful binding of ERCC5 endonuclease 3' to the damage facilitates binding of the ERCC1:ERCC4 (ERCC1:XPF) endonuclease and progression of the NER reaction. | |||
| RAD23 | R-HSA-5691004 (Reactome) | |||
| RFC Heteropentamer | R-HSA-5690213 (Reactome) | |||
| RFC Heteropentamer | R-HSA-6782211 (Reactome) | |||
| RNA
Polymerase II holoenzyme complex (hyperphosphorylated) | Arrow | R-HSA-6782234 (Reactome) | ||
| RNA Polymerase II
holoenzyme complex (unphosphorylated) | R-HSA-6781818 (Reactome) | |||
| RNF111 | mim-catalysis | R-HSA-6790487 (Reactome) | ||
| RPA heterotrimer | R-HSA-5689317 (Reactome) | |||
| RPA heterotrimer | R-HSA-6782138 (Reactome) | |||
| SUMO1,2,3:UBE2I | R-HSA-6790454 (Reactome) | |||
| TC-NER
incision complex: 5'-incised damaged DNA:trimmed nascent mRNA:(PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | Arrow | R-HSA-6782211 (Reactome) | ||
| TC-NER
incision complex: 5'-incised damaged DNA:trimmed nascent mRNA:(PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | R-HSA-6782224 (Reactome) | |||
| TC-NER
incision complex: 5'-incised damaged DNA:trimmed nascent mRNA:(PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | mim-catalysis | R-HSA-6782224 (Reactome) | ||
| TC-NER
post-incision complex:SSB-dsDNA:trimmed nascent mRNA: (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | Arrow | R-HSA-6782208 (Reactome) | ||
| TC-NER
post-incision complex:SSB-dsDNA:trimmed nascent mRNA: (PCNA:POLD,POLE), (MonoUb:K164-PCNA:POLK):RPA:RFC | R-HSA-6782227 (Reactome) | |||
| TC-NER
post-incision complex:incised DNA without lesion:trimmed nascent mRNA:PCNA:(PCNA:POLD,POLE),(MonoUb:K164-PCNA:POLK):RPA:RFC | Arrow | R-HSA-6782224 (Reactome) | ||
| TC-NER
post-incision complex:incised DNA without lesion:trimmed nascent mRNA:PCNA:(PCNA:POLD,POLE),(MonoUb:K164-PCNA:POLK):RPA:RFC | R-HSA-6782208 (Reactome) | |||
| TC-NER
post-incision complex:incised DNA without lesion:trimmed nascent mRNA:PCNA:(PCNA:POLD,POLE),(MonoUb:K164-PCNA:POLK):RPA:RFC | mim-catalysis | R-HSA-6782208 (Reactome) | ||
| TC-NER
pre-incision complex:Open bubble damaged DNA template:RPA:ERCC5:trimmed nascent mRNA | Arrow | R-HSA-6782138 (Reactome) | ||
| TC-NER
pre-incision complex:Open bubble damaged DNA template:RPA:ERCC5:trimmed nascent mRNA | R-HSA-6782141 (Reactome) | |||
| TC-NER incision
complex:5'-incised damaged DNA:trimmed nascent mRNA | Arrow | R-HSA-6782204 (Reactome) | ||
| TC-NER incision
complex:5'-incised damaged DNA:trimmed nascent mRNA | R-HSA-6782211 (Reactome) | |||
| TC-NER incision complex | Arrow | R-HSA-6782141 (Reactome) | ||
| TC-NER incision complex | R-HSA-6782204 (Reactome) | |||
| TC-NER incision complex | mim-catalysis | R-HSA-6782204 (Reactome) | ||
| TC-NER post-incision
complex:dsDNA with transcription bubble | Arrow | R-HSA-6782227 (Reactome) | ||
| TC-NER post-incision
complex:dsDNA with transcription bubble | R-HSA-6782234 (Reactome) | |||
| TC-NER pre-incision
complex:Open bubble damaged DNA template:trimmed nascent mRNA | Arrow | R-HSA-6782131 (Reactome) | ||
| TC-NER pre-incision
complex:Open bubble damaged DNA template:trimmed nascent mRNA | R-HSA-6782138 (Reactome) | |||
| TC-NER pre-incision complex | Arrow | R-HSA-6782069 (Reactome) | ||
| TC-NER pre-incision complex | R-HSA-6782131 (Reactome) | |||
| TC-NER pre-incision complex | mim-catalysis | R-HSA-6782131 (Reactome) | ||
| TCEA1 | Arrow | R-HSA-6782234 (Reactome) | ||
| TCEA1 | R-HSA-6782004 (Reactome) | |||
| TFIIH Core | Arrow | R-HSA-5690988 (Reactome) | ||
| TFIIH | Arrow | R-HSA-6782234 (Reactome) | ||
| TFIIH | R-HSA-5691000 (Reactome) | |||
| TFIIH | R-HSA-6781818 (Reactome) | |||
| UBE2I | Arrow | R-HSA-6790454 (Reactome) | ||
| UBE2N:UBE2V2 | Arrow | R-HSA-6790487 (Reactome) | ||
| USP45 | mim-catalysis | R-HSA-5696465 (Reactome) | ||
| UV-DDB:COP9 Signalosome | R-HSA-5691006 (Reactome) | |||
| UVSSA:USP7 | Arrow | R-HSA-6782234 (Reactome) | ||
| UVSSA:USP7 | R-HSA-6782004 (Reactome) | |||
| Ub,SUMO,K63polyUb:XPC:RAD23:CETN2 | Arrow | R-HSA-6790487 (Reactome) | ||
| Ub,SUMO:XPC:RAD23:CETN2:Open bubble-dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1, PAR-PARP2:CHD1L | Arrow | R-HSA-6790454 (Reactome) | ||
| Ub,SUMO:XPC:RAD23:CETN2:Open bubble-dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1, PAR-PARP2:CHD1L | R-HSA-6790487 (Reactome) | |||
| Ub:ERCC1 | R-HSA-5696465 (Reactome) | |||
| Ub:ERCC6 | Arrow | R-HSA-6782234 (Reactome) | ||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:PAR-PARP1,PAR-PARP2 | Arrow | R-HSA-5696655 (Reactome) | ||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:PAR-PARP1,PAR-PARP2 | R-HSA-5691000 (Reactome) | |||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2:CHD1L | Arrow | R-HSA-5696670 (Reactome) | ||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2:CHD1L | R-HSA-5690996 (Reactome) | |||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2:CHD1L | mim-catalysis | R-HSA-5690996 (Reactome) | ||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2 | Arrow | R-HSA-5689861 (Reactome) | ||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2 | R-HSA-5696670 (Reactome) | |||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH:PAR-PARP1,PAR-PARP2 | Arrow | R-HSA-5691000 (Reactome) | ||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:PAR-UV-DDB:TFIIH:PAR-PARP1,PAR-PARP2 | R-HSA-5689861 (Reactome) | |||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB:PARP1,PARP2 | Arrow | R-HSA-5696664 (Reactome) | ||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB:PARP1,PARP2 | R-HSA-5696655 (Reactome) | |||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB | Arrow | R-HSA-6782943 (Reactome) | ||
| Ub:XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB | R-HSA-5696664 (Reactome) | |||
| Ub:XPC:RAD23:CETN2:Open bubble-dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2:CHD1L | Arrow | R-HSA-5690996 (Reactome) | ||
| Ub:XPC:RAD23:CETN2:Open bubble-dsDNA:PAR-UV-DDB:TFIIH Core:XPA:PAR-PARP1,PAR-PARP2:CHD1L | R-HSA-6790454 (Reactome) | |||
| Ubiquitinated,hyperphosphorylated RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:Ub:ERCC6:ERCC8:DDB1:CUL4:RBX1:UVSSA:USP7:XAB2 complex:XPA:TCEA1:HMGN1:EP300 | Arrow | R-HSA-6782004 (Reactome) | ||
| Ubiquitinated,hyperphosphorylated RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:Ub:ERCC6:ERCC8:DDB1:CUL4:RBX1:UVSSA:USP7:XAB2 complex:XPA:TCEA1:HMGN1:EP300 | R-HSA-6782069 (Reactome) | |||
| Ubiquitinated,hyperphosphorylated RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:Ub:ERCC6:ERCC8:DDB1:CUL4:RBX1:UVSSA:USP7:XAB2 complex:XPA:TCEA1:HMGN1:EP300 | mim-catalysis | R-HSA-6782069 (Reactome) | ||
| Ubiquitinated,hyperphosphorylated RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:Ub:ERCC6:ERCC8:DDB1:CUL4:RBX1 | Arrow | R-HSA-6781867 (Reactome) | ||
| Ubiquitinated,hyperphosphorylated RNA Pol II:Damaged DNA template:nascent mRNA hybrid:TFIIH:Ub:ERCC6:ERCC8:DDB1:CUL4:RBX1 | R-HSA-6782004 (Reactome) | |||
| XAB2 complex | Arrow | R-HSA-6782234 (Reactome) | ||
| XAB2 complex | R-HSA-6782004 (Reactome) | |||
| XPA | Arrow | R-HSA-5690988 (Reactome) | ||
| XPA | Arrow | R-HSA-6782224 (Reactome) | ||
| XPA | R-HSA-5689861 (Reactome) | |||
| XPA | R-HSA-6782004 (Reactome) | |||
| XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB | Arrow | R-HSA-5691006 (Reactome) | ||
| XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB | R-HSA-6782943 (Reactome) | |||
| XPC:RAD23:CETN2:Distorted dsDNA:UV-DDB | mim-catalysis | R-HSA-6782943 (Reactome) | ||
| XPC:RAD23:CETN2 | Arrow | R-HSA-5691004 (Reactome) | ||
| XPC:RAD23:CETN2 | R-HSA-5691006 (Reactome) | |||
| XPC | R-HSA-5691004 (Reactome) | |||
| dNTP | R-HSA-5691001 (Reactome) | |||
| dNTP | R-HSA-6782208 (Reactome) | |||
| dsDNA | Arrow | R-HSA-5690997 (Reactome) | ||
| dsDNA | Arrow | R-HSA-6782234 (Reactome) | ||
| excised DNA fragment with lesion | Arrow | R-HSA-5690988 (Reactome) | ||
| mRNA | Arrow | R-HSA-6782234 (Reactome) | ||
| ribonucleoside triphosphate | R-HSA-6781824 (Reactome) | |||
| ubiquitin | Arrow | R-HSA-5696465 (Reactome) | ||
| ubiquitin | Arrow | R-HSA-6782069 (Reactome) | ||
| ubiquitin | R-HSA-6781867 (Reactome) | |||
| ubiquitin | R-HSA-6782943 (Reactome) |
