Nucleotide excision repair in xeroderma pigmentosum (Homo sapiens)

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3091119282104, 1610141928113, 25209orDNA damage signalingLegend:UV - RadiationDNAMutated XP geneNucleotide lesionStimulation UbiquitylationRPATranscription factor II H (TFIIH)Step 1 - Recognition of damaged DNAThe choice of DNA ligase depends on the DNA polymerase involved in repair synthesis and probably the stage of the cell cycle (Moser et al. 2007).Early chromatin remodelingInhibition of UV-DDB when no UV-damage is present.With UV damage, inhibition is lifted UVRDNA polymerasesTranscription-coupled repairStep 4 - Gap-filling, DNA synthesis and ligationUV-DDBXPC complexDNA lesionUV-damaged DNA TCR-initiation complexDNA unwinding by XPB and XPD helicases91726XAB2RPA2XRCC1BRCA1XPAp52/GTF2H4PARP1HMGN1SLX4IPCHD1L (ALC1)LIG3TTDA/GTF2H5ERCC6POLKRPA1BRCA1USP7Histone H4RPA3Histone H2ARAD18SLX4RNA polymerase IIUVSSAXRCC1TFIISHistone H3POLD1ERCC6 (CSB)POLHCSN (COP9)LIG1XPARAD23B129188, 1322151913, 16, 2112122627RBX1CUL4ACUL4BERCC8 (CSA)DDB1CDK7 MNAT1CCNHXPD/ERCC2XPB/ERCC3p62/GTF2H1p44/GTF2H2p34 /GTF2H3XPF/ERCC1XPG/ERCC4Step 3 - Incision and excision23POLD2POLD3POLD4POLEPOLE2POLE3POLE4PCNARFC1RFC2RFC3RFC4RFC5LigationGlobal genome repairXPE complexRBX1CUL4ACUL4B24XPE (DDB2)DDB116XPCRAD23ACETN25RPARPA3RPA2RPA1In non-replicating cellsIn replicating cellsCSN (COP9)26XPD/ERCC2XPB/ERCC3RPARPA3RPA2RPA1Step 2 - DNA binding and unwinding20


Description

Nucleotide excision repair is a DNA repair mechanism that repairs DNA damaged by UV radiation.

This type of damage produces bulky distortions in the shape of DNA double helix due to the addition of DNA adducts, mostly thymine dimers and 6,4-photoproducts.

Recognition of distortions leads to the removal of a short single-stranded DNA segment that includes the lesion, creating a single-strand gap in the DNA, which is subsequently filled in by DNA polymerase, which uses the undamaged strand as a template. NER can be divided into two subpathways (Global genomic NER and Transcription coupled NER) that differ only in their recognition of helix-distorting DNA damage. Nucleotide excision repair has more complexity in eukaryotes.

Nucleotide excision repair (NER) is a particularly important DNA repair mechanism as evidenced by the severe human diseases that result from in-born genetic mutations of NER proteins including Xeroderma pigmentosum and Cockayne's syndrome.

This pathway was adapted from KEGG, REPAIRtoire and Wikipedia. The pathway layout is based on KEGG.

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Bibliography

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  2. Zlatanou A, Despras E, Braz-Petta T, Boubakour-Azzouz I, Pouvelle C, Stewart GS, Nakajima S, Yasui A, Ishchenko AA, Kannouche PL; ''The hMsh2-hMsh6 complex acts in concert with monoubiquitinated PCNA and Pol η in response to oxidative DNA damage in human cells.''; Mol Cell, 2011 PubMed Europe PMC Scholia
  3. Luijsterburg MS, Lindh M, Acs K, Vrouwe MG, Pines A, van Attikum H, Mullenders LH, Dantuma NP; ''DDB2 promotes chromatin decondensation at UV-induced DNA damage.''; J Cell Biol, 2012 PubMed Europe PMC Scholia
  4. Sugasawa K, Okuda Y, Saijo M, Nishi R, Matsuda N, Chu G, Mori T, Iwai S, Tanaka K, Hanaoka F; ''UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex.''; Cell, 2005 PubMed Europe PMC Scholia
  5. Renaud E, Miccoli L, Zacal N, Biard DS, Craescu CT, Rainbow AJ, Angulo JF; ''Differential contribution of XPC, RAD23A, RAD23B and CENTRIN 2 to the UV-response in human cells.''; DNA Repair (Amst), 2011 PubMed Europe PMC Scholia
  6. Lee J, Zhou P; ''DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase.''; Mol Cell, 2007 PubMed Europe PMC Scholia
  7. Zhang ET, He Y, Grob P, Fong YW, Nogales E, Tjian R; ''Architecture of the human XPC DNA repair and stem cell coactivator complex.''; Proc Natl Acad Sci U S A, 2015 PubMed Europe PMC Scholia
  8. Vasquez KM, Christensen J, Li L, Finch RA, Glazer PM; ''Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions.''; Proc Natl Acad Sci U S A, 2002 PubMed Europe PMC Scholia
  9. Okuda M, Nakazawa Y, Guo C, Ogi T, Nishimura Y; ''Common TFIIH recruitment mechanism in global genome and transcription-coupled repair subpathways.''; Nucleic Acids Res, 2017 PubMed Europe PMC Scholia
  10. 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.''; Genes Dev, 2006 PubMed Europe PMC Scholia
  11. 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.''; EMBO J, 2008 PubMed Europe PMC Scholia
  12. Pines A, Vrouwe MG, Marteijn JA, Typas D, Luijsterburg MS, Cansoy M, Hensbergen P, Deelder A, de Groot A, Matsumoto S, Sugasawa K, Thoma N, Vermeulen W, Vrieling H, Mullenders L; ''PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1.''; J Cell Biol, 2012 PubMed Europe PMC Scholia
  13. Borszéková Pulzová L, Ward TA, Chovanec M; ''XPA: DNA Repair Protein of Significant Clinical Importance.''; Int J Mol Sci, 2020 PubMed Europe PMC Scholia
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  16. 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.''; Mol Cell Biol, 2010 PubMed Europe PMC Scholia
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  18. 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.''; Mol Cell, 2007 PubMed Europe PMC Scholia
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History

View all...
CompareRevisionActionTimeUserComment
119169view16:21, 19 June 2021NataliehCorrected a mistake
119168view16:20, 19 June 2021NataliehDeleted an unwanted node
119167view16:19, 19 June 2021NataliehMarked XP mutations
119166view15:53, 19 June 2021NataliehAdded missing links between some nodes
118858view12:07, 2 June 2021NataliehDeleted an unwanted node
118855view11:34, 2 June 2021FehrhartOntology Term : 'xeroderma pigmentosum' added !
118854view11:33, 2 June 2021FehrhartModified title
118781view16:50, 1 June 2021NataliehModified title
118767view15:30, 1 June 2021Natalieh
118766view15:30, 1 June 2021Natalieh
118765view15:25, 1 June 2021NataliehNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
BRCA1GeneProductBRCA1 (HGNC)
BRCA1GeneProductENSG00000012048 (Ensembl)
CCNHGeneProductENSG00000134480 (Ensembl)
CDK7 GeneProductENSG00000134058 (Ensembl) This subcomplex dissociates after XPA binds
CETN2GeneProductENSG00000147400 (Ensembl) "CENTRIN 2 enhances the affinity of XPC/RAD23B for DNA distortions"
CHD1L (ALC1)GeneProductENSG00000131778 (Ensembl)
CSN (COP9)ProteinA0A096LP07 (Uniprot-TrEMBL)
CUL4AGeneProductENSG00000139842 (Ensembl)
CUL4BGeneProductENSG00000158290 (Ensembl)
DDB1GeneProductENSG00000167986 (Ensembl)
ERCC6 (CSB) GeneProductENSG00000225830 (Ensembl) https://reactome.org/PathwayBrowser/#/R-HSA-5696398&SEL=R-HSA-6781823&PATH=R-HSA-73894
ERCC6GeneProductENSG00000225830 (Ensembl)
ERCC8 (CSA)GeneProductENSG00000049167 (Ensembl)
HMGN1GeneProductENSG00000205581 (Ensembl)
Histone H2AProteinA0A024R017 (Uniprot-TrEMBL)
Histone H3ProteinB2R4P9 (Uniprot-TrEMBL)
Histone H4ProteinB2R4R0 (Uniprot-TrEMBL)
LIG1GeneProductENSG00000105486 (Ensembl)
LIG3GeneProductENSG00000005156 (Ensembl)
MNAT1GeneProductENSG00000020426 (Ensembl)
PARP1GeneProductPARP1 (HGNC)
PCNAGeneProductENSG00000132646 (Ensembl)
POLD1GeneProductENSG00000062822 (Ensembl)
POLD2GeneProductENSG00000106628 (Ensembl)
POLD3GeneProductENSG00000077514 (Ensembl) DNA polymerase delta
POLD4GeneProductENSG00000175482 (Ensembl)
POLE2GeneProductENSG00000100479 (Ensembl)
POLE3GeneProductENSG00000148229 (Ensembl)
POLE4GeneProductENSG00000115350 (Ensembl)
POLEGeneProductENSG00000177084 (Ensembl)
POLHGeneProductENSG00000170734 (Ensembl) DNA polymerase eta
POLKGeneProductENSG00000122008 (Ensembl) DNA polymerase kappa
RAD18GeneProductRAD18 (HGNC)
RAD23AGeneProductENSG00000179262 (Ensembl)
RAD23BGeneProductENSG00000119318 (Ensembl)
RBX1GeneProductENSG00000100387 (Ensembl)
RFC1GeneProductENSG00000035928 (Ensembl)
RFC2GeneProductENSG00000049541 (Ensembl)
RFC3GeneProductENSG00000133119 (Ensembl)
RFC4GeneProductENSG00000163918 (Ensembl)
RFC5GeneProductENSG00000111445 (Ensembl)
RNA polymerase IIProtein
RPA1GeneProductENSG00000132383 (Ensembl)
RPA2GeneProductENSG00000117748 (Ensembl)
RPA3GeneProductENSG00000106399 (Ensembl)
SLX4GeneProductENSG00000188827 (Ensembl)
SLX4IPGeneProductENSG00000149346 (Ensembl)
TFIISGeneProduct
TTDA/GTF2H5GeneProductENSG00000272047 (Ensembl)
USP7GeneProductENSG00000187555 (Ensembl)
UVSSAGeneProductENSG00000163945 (Ensembl)
XAB2GeneProductENSG00000076924 (Ensembl)
XPAGeneProductENSG00000136936 (Ensembl)
XPB/ERCC3GeneProductENSG00000163161 (Ensembl)
XPCGeneProductENSG00000154767 (Ensembl)
XPD/ERCC2GeneProductENSG00000104884 (Ensembl)
XPE (DDB2)GeneProductENSG00000134574 (Ensembl) Structural analysis revealed that DDB2 interacts extensively with DNA containing a lesion, while DDB1 stabilizes DDB2 but does not bind to DNA. DDB2 unwinds and kinks the DNA, and the lesion is consequently flipped out and partially held in a shallow binding pocket of DDB2
XPF/ERCC1GeneProductENSG00000012061 (Ensembl)
XPG/ERCC4GeneProductENSG00000175595 (Ensembl)
XRCC1GeneProductENSG00000073050 (Ensembl)
p34 /GTF2H3GeneProductENSG00000111358 (Ensembl)
p44/GTF2H2GeneProductENSG00000145736 (Ensembl)
p52/GTF2H4GeneProductENSG00000213780 (Ensembl)
p62/GTF2H1GeneProductENSG00000110768 (Ensembl)

Annotated Interactions

No annotated interactions

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