Base excision repair is initiated by DNA glycosylases that hydrolytically cleave the base-deoxyribose glycosyl bond of a damaged nucleotide residue, releasing the damaged base (Lindahl and Wood 1999, Sokhansanj et al. 2002).
View original pathway at Reactome.
Semlow DR, Zhang J, Budzowska M, Drohat AC, Walter JC.; ''Replication-Dependent Unhooking of DNA Interstrand Cross-Links by the NEIL3 Glycosylase.''; PubMedEurope PMCScholia
Samson L, Derfler B, Boosalis M, Call K.; ''Cloning and characterization of a 3-methyladenine DNA glycosylase cDNA from human cells whose gene maps to chromosome 16.''; PubMedEurope PMCScholia
Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A, Le Coz M, Devarajan K, Wessels A, Soprano D, Abramowitz LK, Bartolomei MS, Rambow F, Bassi MR, Bruno T, Fanciulli M, Renner C, Klein-Szanto AJ, Matsumoto Y, Kobi D, Davidson I, Alberti C, Larue L, Bellacosa A.; ''Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair.''; PubMedEurope PMCScholia
Janik J, Swoboda M, Janowska B, Cieśla JM, Gackowski D, Kowalewski J, Olinski R, Tudek B, Speina E.; ''8-Oxoguanine incision activity is impaired in lung tissues of NSCLC patients with the polymorphism of OGG1 and XRCC1 genes.''; PubMedEurope PMCScholia
Liu M, Bandaru V, Holmes A, Averill AM, Cannan W, Wallace SS.; ''Expression and purification of active mouse and human NEIL3 proteins.''; PubMedEurope PMCScholia
Slupska MM, Baikalov C, Luther WM, Chiang JH, Wei YF, Miller JH.; ''Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage.''; PubMedEurope PMCScholia
Zhou J, Chan J, Lambelé M, Yusufzai T, Stumpff J, Opresko PL, Thali M, Wallace SS.; ''NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis.''; PubMedEurope PMCScholia
Smirnova E, Toueille M, Markkanen E, Hübscher U.; ''The human checkpoint sensor and alternative DNA clamp Rad9-Rad1-Hus1 modulates the activity of DNA ligase I, a component of the long-patch base excision repair machinery.''; PubMedEurope PMCScholia
Bjorâs M, Luna L, Johnsen B, Hoff E, Haug T, Rognes T, Seeberg E.; ''Opposite base-dependent reactions of a human base excision repair enzyme on DNA containing 7,8-dihydro-8-oxoguanine and abasic sites.''; PubMedEurope PMCScholia
Evans MD, Dizdaroglu M, Cooke MS.; ''Oxidative DNA damage and disease: induction, repair and significance.''; PubMedEurope PMCScholia
Ohtsubo T, Nishioka K, Imaiso Y, Iwai S, Shimokawa H, Oda H, Fujiwara T, Nakabeppu Y.; ''Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria.''; PubMedEurope PMCScholia
Hashimoto H, Hong S, Bhagwat AS, Zhang X, Cheng X.; ''Excision of 5-hydroxymethyluracil and 5-carboxylcytosine by the thymine DNA glycosylase domain: its structural basis and implications for active DNA demethylation.''; PubMedEurope PMCScholia
Wu P, Qiu C, Sohail A, Zhang X, Bhagwat AS, Cheng X.; ''Mismatch repair in methylated DNA. Structure and activity of the mismatch-specific thymine glycosylase domain of methyl-CpG-binding protein MBD4.''; PubMedEurope PMCScholia
Dizdaroglu M, Laval J, Boiteux S.; ''Substrate specificity of the Escherichia coli endonuclease III: excision of thymine- and cytosine-derived lesions in DNA produced by radiation-generated free radicals.''; PubMedEurope PMCScholia
Wang W, Brandt P, Rossi ML, Lindsey-Boltz L, Podust V, Fanning E, Sancar A, Bambara RA.; ''The human Rad9-Rad1-Hus1 checkpoint complex stimulates flap endonuclease 1.''; PubMedEurope PMCScholia
Luna L, Bjørås M, Hoff E, Rognes T, Seeberg E.; ''Cell-cycle regulation, intracellular sorting and induced overexpression of the human NTH1 DNA glycosylase involved in removal of formamidopyrimidine residues from DNA.''; PubMedEurope PMCScholia
Haushalter KA, Todd Stukenberg MW, Kirschner MW, Verdine GL.; ''Identification of a new uracil-DNA glycosylase family by expression cloning using synthetic inhibitors.''; PubMedEurope PMCScholia
Boldogh I, Milligan D, Lee MS, Bassett H, Lloyd RS, McCullough AK.; ''hMYH cell cycle-dependent expression, subcellular localization and association with replication foci: evidence suggesting replication-coupled repair of adenine:8-oxoguanine mispairs.''; PubMedEurope PMCScholia
Hazra TK, Izumi T, Boldogh I, Imhoff B, Kow YW, Jaruga P, Dizdaroglu M, Mitra S.; ''Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA.''; PubMedEurope PMCScholia
Ali K, Mahjabeen I, Sabir M, Mehmood H, Kayani MA.; ''OGG1 Mutations and Risk of Female Breast Cancer: Meta-Analysis and Experimental Data.''; PubMedEurope PMCScholia
Dizdaroglu M, Karakaya A, Jaruga P, Slupphaug G, Krokan HE.; ''Novel activities of human uracil DNA N-glycosylase for cytosine-derived products of oxidative DNA damage.''; PubMedEurope PMCScholia
Zhu C, Lu L, Zhang J, Yue Z, Song J, Zong S, Liu M, Stovicek O, Gao YQ, Yi C.; ''Tautomerization-dependent recognition and excision of oxidation damage in base-excision DNA repair.''; PubMedEurope PMCScholia
Parikh SS, Mol CD, Slupphaug G, Bharati S, Krokan HE, Tainer JA.; ''Base excision repair initiation revealed by crystal structures and binding kinetics of human uracil-DNA glycosylase with DNA.''; PubMedEurope PMCScholia
Moréra S, Grin I, Vigouroux A, Couvé S, Henriot V, Saparbaev M, Ishchenko AA.; ''Biochemical and structural characterization of the glycosylase domain of MBD4 bound to thymine and 5-hydroxymethyuracil-containing DNA.''; PubMedEurope PMCScholia
Kershaw RM, Hodges NJ.; ''Repair of oxidative DNA damage is delayed in the Ser326Cys polymorphic variant of the base excision repair protein OGG1.''; PubMedEurope PMCScholia
Yamane A, Kohno T, Ito K, Sunaga N, Aoki K, Yoshimura K, Murakami H, Nojima Y, Yokota J.; ''Differential ability of polymorphic OGG1 proteins to suppress mutagenesis induced by 8-hydroxyguanine in human cell in vivo.''; PubMedEurope PMCScholia
Petronzelli F, Riccio A, Markham GD, Seeholzer SH, Genuardi M, Karbowski M, Yeung AT, Matsumoto Y, Bellacosa A.; ''Investigation of the substrate spectrum of the human mismatch-specific DNA N-glycosylase MED1 (MBD4): fundamental role of the catalytic domain.''; PubMedEurope PMCScholia
Radicella JP, Dherin C, Desmaze C, Fox MS, Boiteux S.; ''Cloning and characterization of hOGG1, a human homolog of the OGG1 gene of Saccharomyces cerevisiae.''; PubMedEurope PMCScholia
Petronzelli F, Riccio A, Markham GD, Seeholzer SH, Stoerker J, Genuardi M, Yeung AT, Matsumoto Y, Bellacosa A.; ''Biphasic kinetics of the human DNA repair protein MED1 (MBD4), a mismatch-specific DNA N-glycosylase.''; PubMedEurope PMCScholia
Hazra TK, Kow YW, Hatahet Z, Imhoff B, Boldogh I, Mokkapati SK, Mitra S, Izumi T.; ''Identification and characterization of a novel human DNA glycosylase for repair of cytosine-derived lesions.''; PubMedEurope PMCScholia
Dosanjh MK, Roy R, Mitra S, Singer B.; ''1,N6-ethenoadenine is preferred over 3-methyladenine as substrate by a cloned human N-methylpurine-DNA glycosylase (3-methyladenine-DNA glycosylase).''; PubMedEurope PMCScholia
Neddermann P, Jiricny J.; ''The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells.''; PubMedEurope PMCScholia
Sokhansanj BA, Rodrigue GR, Fitch JP, Wilson DM.; ''A quantitative model of human DNA base excision repair. I. Mechanistic insights.''; PubMedEurope PMCScholia
Balakrishnan L, Brandt PD, Lindsey-Boltz LA, Sancar A, Bambara RA.; ''Long patch base excision repair proceeds via coordinated stimulation of the multienzyme DNA repair complex.''; PubMedEurope PMCScholia
Prasad R, Lavrik OI, Kim SJ, Kedar P, Yang XP, Vande Berg BJ, Wilson SH.; ''DNA polymerase beta -mediated long patch base excision repair. Poly(ADP-ribose)polymerase-1 stimulates strand displacement DNA synthesis.''; PubMedEurope PMCScholia
Moritz E, Pauly K, Bravard A, Hall J, Radicella JP, Epe B.; ''hOGG1-Cys326 variant cells are hypersensitive to DNA repair inhibition by nitric oxide.''; PubMedEurope PMCScholia
Miyabe I, Zhang QM, Kino K, Sugiyama H, Takao M, Yasui A, Yonei S.; ''Identification of 5-formyluracil DNA glycosylase activity of human hNTH1 protein.''; PubMedEurope PMCScholia
Klungland A, Lindahl T.; ''Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1).''; PubMedEurope PMCScholia
Hu J, de Souza-Pinto NC, Haraguchi K, Hogue BA, Jaruga P, Greenberg MM, Dizdaroglu M, Bohr VA.; ''Repair of formamidopyrimidines in DNA involves different glycosylases: role of the OGG1, NTH1, and NEIL1 enzymes.''; PubMedEurope PMCScholia
Dherin C, Radicella JP, Dizdaroglu M, Boiteux S.; ''Excision of oxidatively damaged DNA bases by the human alpha-hOgg1 protein and the polymorphic alpha-hOgg1(Ser326Cys) protein which is frequently found in human populations.''; PubMedEurope PMCScholia
Martin PR, Couvé S, Zutterling C, Albelazi MS, Groisman R, Groisman R, Matkarimov BT, Parsons JL, Elder RH, Saparbaev MK.; ''The Human DNA glycosylases NEIL1 and NEIL3 Excise Psoralen-Induced DNA-DNA Cross-Links in a Four-Stranded DNA Structure.''; PubMedEurope PMCScholia
Plotz G, Casper M, Raedle J, Hinrichsen I, Heckel V, Brieger A, Trojan J, Zeuzem S.; ''MUTYH gene expression and alternative splicing in controls and polyposis patients.''; PubMedEurope PMCScholia
Masuda Y, Bennett RA, Demple B.; ''Dynamics of the interaction of human apurinic endonuclease (Ape1) with its substrate and product.''; PubMedEurope PMCScholia
O'Connor TR.; ''Purification and characterization of human 3-methyladenine-DNA glycosylase.''; PubMedEurope PMCScholia
Aburatani H, Hippo Y, Ishida T, Takashima R, Matsuba C, Kodama T, Takao M, Yasui A, Yamamoto K, Asano M.; ''Cloning and characterization of mammalian 8-hydroxyguanine-specific DNA glycosylase/apurinic, apyrimidinic lyase, a functional mutM homologue.''; PubMedEurope PMCScholia
Rosenquist TA, Zharkov DO, Grollman AP.; ''Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase.''; PubMedEurope PMCScholia
Berdal KG, Johansen RF, Seeberg E.; ''Release of normal bases from intact DNA by a native DNA repair enzyme.''; PubMedEurope PMCScholia
Ikeda S, Biswas T, Roy R, Izumi T, Boldogh I, Kurosky A, Sarker AH, Seki S, Mitra S.; ''Purification and characterization of human NTH1, a homolog of Escherichia coli endonuclease III. Direct identification of Lys-212 as the active nucleophilic residue.''; PubMedEurope PMCScholia
Shinmura K, Yamaguchi S, Saitoh T, Takeuchi-Sasaki M, Kim SR, Nohmi T, Yokota J.; ''Adenine excisional repair function of MYH protein on the adenine:8-hydroxyguanine base pair in double-stranded DNA.''; PubMedEurope PMCScholia
Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T.; ''Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein.''; PubMedEurope PMCScholia
Saparbaev M, Laval J.; ''Excision of hypoxanthine from DNA containing dIMP residues by the Escherichia coli, yeast, rat, and human alkylpurine DNA glycosylases.''; PubMedEurope PMCScholia
Masaoka A, Matsubara M, Hasegawa R, Tanaka T, Kurisu S, Terato H, Ohyama Y, Karino N, Matsuda A, Ide H.; ''Mammalian 5-formyluracil-DNA glycosylase. 2. Role of SMUG1 uracil-DNA glycosylase in repair of 5-formyluracil and other oxidized and deaminated base lesions.''; PubMedEurope PMCScholia
Dianova II, Bohr VA, Dianov GL.; ''Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair.''; PubMedEurope PMCScholia
Bruner SD, Norman DP, Verdine GL.; ''Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA.''; PubMedEurope PMCScholia
Saparbaev M, Kleibl K, Laval J.; ''Escherichia coli, Saccharomyces cerevisiae, rat and human 3-methyladenine DNA glycosylases repair 1,N6-ethenoadenine when present in DNA.''; PubMedEurope PMCScholia
Dizdaroglu M, Karahalil B, Sentürker S, Buckley TJ, Roldán-Arjona T.; ''Excision of products of oxidative DNA base damage by human NTH1 protein.''; PubMedEurope PMCScholia
Roldán-Arjona T, Wei YF, Carter KC, Klungland A, Anselmino C, Wang RP, Augustus M, Lindahl T.; ''Molecular cloning and functional expression of a human cDNA encoding the antimutator enzyme 8-hydroxyguanine-DNA glycosylase.''; PubMedEurope PMCScholia
Krokeide SZ, Laerdahl JK, Salah M, Luna L, Cederkvist FH, Fleming AM, Burrows CJ, Dalhus B, Bjørås M.; ''Human NEIL3 is mainly a monofunctional DNA glycosylase removing spiroimindiohydantoin and guanidinohydantoin.''; PubMedEurope PMCScholia
Nishioka K, Ohtsubo T, Oda H, Fujiwara T, Kang D, Sugimachi K, Nakabeppu Y.; ''Expression and differential intracellular localization of two major forms of human 8-oxoguanine DNA glycosylase encoded by alternatively spliced OGG1 mRNAs.''; PubMedEurope PMCScholia
Wilson DM, Takeshita M, Grollman AP, Demple B.; ''Incision activity of human apurinic endonuclease (Ape) at abasic site analogs in DNA.''; PubMedEurope PMCScholia
Janssen K, Schlink K, Götte W, Hippler B, Kaina B, Oesch F.; ''DNA repair activity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes is not dependent on genetic polymorphism Ser326/Cys326.''; PubMedEurope PMCScholia
Bennett RA, Wilson DM, Wong D, Demple B.; ''Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway.''; PubMedEurope PMCScholia
Wiederhold L, Leppard JB, Kedar P, Karimi-Busheri F, Rasouli-Nia A, Weinfeld M, Tomkinson AE, Izumi T, Prasad R, Wilson SH, Mitra S, Hazra TK.; ''AP endonuclease-independent DNA base excision repair in human cells.''; PubMedEurope PMCScholia
Neddermann P, Gallinari P, Lettieri T, Schmid D, Truong O, Hsuan JJ, Wiebauer K, Jiricny J.; ''Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase.''; PubMedEurope PMCScholia
Guan X, Bai H, Shi G, Theriot CA, Hazra TK, Mitra S, Lu AL.; ''The human checkpoint sensor Rad9-Rad1-Hus1 interacts with and stimulates NEIL1 glycosylase.''; PubMedEurope PMCScholia
Shinmura K, Kato H, Kawanishi Y, Goto M, Tao H, Inoue Y, Nakamura S, Sugimura H.; ''NEIL1 p.Gln282Stop variant is predominantly localized in the cytoplasm and exhibits reduced activity in suppressing mutations.''; PubMedEurope PMCScholia
Lau AY, Schärer OD, Samson L, Verdine GL, Ellenberger T.; ''Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA: mechanisms for nucleotide flipping and base excision.''; PubMedEurope PMCScholia
Das A, Wiederhold L, Leppard JB, Kedar P, Prasad R, Wang H, Boldogh I, Karimi-Busheri F, Weinfeld M, Tomkinson AE, Wilson SH, Mitra S, Hazra TK.; ''NEIL2-initiated, APE-independent repair of oxidized bases in DNA: Evidence for a repair complex in human cells.''; PubMedEurope PMCScholia
Vickers MA, Vyas P, Harris PC, Simmons DL, Higgs DR.; ''Structure of the human 3-methyladenine DNA glycosylase gene and localization close to the 16p telomere.''; PubMedEurope PMCScholia
Hang B, Medina M, Fraenkel-Conrat H, Singer B.; ''A 55-kDa protein isolated from human cells shows DNA glycosylase activity toward 3,N4-ethenocytosine and the G/T mismatch.''; PubMedEurope PMCScholia
This isoform of MUTYH uses exon 1-alpha and the exon 3 splice donor site variant-3. This is one of the most abundant MUTYH transcripts, while the transcripts that corresponds to the canonical UniProt sequence and to the longest NCBI transcript of MUTYH are rare or not present (Plotz et al. 2012).
Resolution of AP sites can occur through the single nucleotide replacement pathway or through the multiple nucleotide patch replacement pathway, also known as the long-patch base excision repair (BER). Except for the APEX1-independent resolution of AP sites via single nucleotide base excision repair mediated by NEIL1 or NEIL2 (Wiederhold et al. 2004, Das et al. 2006), single nucleotide and multiple-nucleotide patch replacement pathways are both initiated by APEX1-mediated displacement of DNA glycosylases and cleavage of the damaged DNA strand by APEX1 immediately 5' to the AP site (Wilson et al. 1995, Bennett et al. 1997, Masuda et al. 1998). The BER proceeds via the single nucleotide replacement when the AP (apurinic/apyrimidinic) deoxyribose residue at the 5' end of the APEX1-created single strand break (SSB) (5'dRP) can be removed by the 5'-exonuclease activity of DNA polymerase beta (POLB) (Bennett et al. 1997). POLB fills the created single nucleotide gap by adding a nucleotide complementary to the undamaged DNA strand to the 3' end of the SSB. The SSB is subsequently ligated by DNA ligase III (LIG3) which, in complex with XRCC1, is recruited to the BER site by an XRCC1-mediated interaction with POLB (Kubota et al. 1996). BER proceeds via the multiple-nucleotide patch replacement pathway when the AP residue at the 5' end of the APEX1-created SSB undergoes oxidation-related damage (5'ddRP) and cannot be cleaved by POLB (Klungland and Lindahl 1997). Long-patch BER can be completed by POLB-mediated DNA strand displacement synthesis in the presence of PARP1 or PARP2, FEN1 and DNA ligase I (LIG1) (Prasad et al. 2001). When the PCNA-containing replication complex is available, as is the case with cells in S-phase of the cell cycle, DNA strand displacement synthesis is catalyzed by DNA polymerase delta (POLD) or DNA polymerase epsilon (POLE) complexes, in the presence of PCNA, RPA, RFC, APEX1, FEN1 and LIG1 (Klungland and Lindahl 1997, Dianova et al. 2001). It is likely that the 9-1-1 repair complex composed of HUS1, RAD1 and RAD9 interacts with and coordinates components of BER, but the exact mechanism and timing have not been elucidated (Wang et al. 2004, Smirnova et al. 2005, Guan et al. 2007, Balakrishnan et al. 2009).
UNG, a uracil DNA glycosylase, recognizes DNA damage that converts cytosine to uracil through deamination, creating a U:G base pair. UNG also recognizes U:A base pairs created when dUMP is misincorporated during DNA synthesis. The UNG transcription isoform 2, labeled as UNG-1 and also known as UDG2, functions in the nucleus, while the UNG transcription isoform 1, which is not annotated here, functions in mitochondria (Parikh et al. 1998).
TDG is a G/T mismatch-specific thymine DNA glycosylase that recognizes and binds thymine mispaired with guanine. G:T mispairs occur when 5-methylcytosine deaminates into thymine. Besides being mutagenic, conversion of 5-methylcytosine into thymine may also affect gene expression by changing the DNA methylation pattern. TDG shows a preference for G:T mispairs in CpG islands (Neddermann and Jiricny 1993, Neddermann et al. 1996). TDG ortholog knockout is embryonic lethal in mice, where it is implicated in protection of CpG islands from hypermethylation and active demethylation of tissue-specific developmentally and homornally regulated promoters and enhancers (Cortellino et al. 2011).
TDG, a G/T mismatch-specific thymine DNA glycosylase, recognizes and binds uracil mispaired with guanine. G:U mispairs occur after cytosine undergoes spontaneous deamination and converts to uracil (Neddermann and Jiricny 1993, Hashimoto et al. 2012).
SMUG1, a single-strand selective monofunctional uracil DNA glycosylase, recognizes and binds uracil residues in the DNA. SMUG1 shows a preference for single-strand DNA, although it also recognizes A:U and G:U pairs in double-strand DNA (Haushalter et al. 1999, Masaoka et al. 2003).
MBD4 (MED1; methyl-CpG-binding domain protein 4) recognizes and binds uracil mispaired with guanine at non-methylated CpG islands. G:U mispairs are generated by oxidative deamination of cytosine (Petronzelli et al. 2000).
MBD4 (MED1; methyl-CpG-binding domain protein 4) recognizes and binds thymine mispaired with guanine in CpG islands. G:T mispair is generated by oxidative deamination of 5-methylcytosine (Petronzelli et al. 2000). MBD4 contains two DNA binding domains: an N-terminal methyl-CpG binding domain (MBD) and a C-terminal mismatch-specific glycosylase domain (Wu et al. 2003). MBD4 catalytic domain uses a flipping mechanism to extrude the thymine from the helix and thereby detect G:T mispairs (Morera et al. 2012).
NTHL1 (hNTH1; endonuclease III-like protein 1) recognizes and binds cytosine glycol (5,6-dihydroxycytosine), a product of DNA damaging cytosine oxidation (Dizdaroglu et al. 1999).
TDG, a G/T mismatch-specific DNA glycosylase, recognizes and binds ethenocytosine paired with guanine. Ethenocytosine is an etheno-adduct of cytosine, generated by peroxidation of the cytosine ring (Hang et al. 1998).
NTHL1 (hNTH1; endonuclease III-like protein 1) is a human ortholog of E. coli DNA repair enzyme Nth1. NTHL1 recognizes and binds thymine glycol, generated by thymine oxidation (Ikeda et al. 1998, Dizdaroglu et al. 1999, Myabe et al. 2002).
NTHL1 (hNTH1; endonuclease III-like protein 1) recognizes and binds dihydrouracil paired with guanine in the double strand DNA (Ikeda et al. 1998). 5,6-dihydrouracil is a form of DNA damage produced by ionizing radiation under anoxic conditions, so that cytosine is deaminated and C5-C6 double bond in the pyrimidine ring is saturated with hydrogen. 5,6-dihydrouracil mispairs with adenine, leading to G:C -> A:T transitions (Dizdaroglu et al. 1993).
NTHL1 (hNTH1; endonuclease III-like protein 1) recognizes and binds 4,6-diamino-5-formamidopyrimidine (FapyA), an imidazole ring-opened adenine derivative (Luna et al. 2000, Hu et al. 2005). FapyA is formed during oxidative stress when hydroxyl radicals attack adenine, followed by one-electron reduction of the hydroxyl adduct radicals (Evans et al. 2004).
UNG, a DNA uracil glycosylase, excises the uracil base generated when a DNA damaging agent deaminates cytosine (creating a U:G base pair) or when dUMP is misincorporated during DNA synthesis (creating a U:A base pair). UNG scans the DNA for damage by kinking and compressing the DNA phosphate backbone with a serine-proline pinch, which causes uracil to flip out at the phosphate-sugar junction into the recognition pocket of the UNG. The subsequent excision of uracil creates an apurinic/apyrimidinic (AP) site in the DNA (Parikh et al. 1998).
UNG, a DNA uracil glycosylase, cleaves 5-hydroxyuracil, generated by cytosine oxidation, from the DNA phosphate backbone, creating an apurinic/apyrimidinic (AP) site in the DNA (Dizdaroglu et al. 1996).
TDG is a G/T mismatch-specific thymine DNA glycosylase that cleaves uracil mispaired with guanine as a consequence of cytosine deamination, leaving an apurinic/apyrimidinic (AP) site in the DNA (Neddermann and Jiricny 1993, Hashimoto et al. 2012).
TDG, a G/T mismatch-specific thymine DNA glycosylase, cleaves thymine, generated through 5-methylcytosine deamination and mispaired with guanine, from the DNA sugar-phosphate backbone, leaving an apurinic/apyrimidinic (AP) site (Neddermann and Jiricny 1993, Neddermann et al. 1996).
SMUG1 is a single-strand selective monofunctional uracil DNA glycosylase that cleaves uracil from the sugar phosphate backbone of DNA. SMUG1 has the highest preference for uracil in single strand DNA, followed by A:U and then G:U pairs in double strand DNA (Haushalter et al. 1999, Masaoka et al. 2003).
NTHL1 (hNTH1; endonuclease III-like protein 1) cleaves oxidized thymine in the form of thymine glycol from DNA sugar-phosphate backbone and acts as a beta lyase to cleave the DNA sugar-phosphate backbone 5' to the apurinic/apyrimidinic (AP) site generated in the glycolysis step (Ikeda et al. 1998, Dizdaroglu et al. 1999, Miyabe et al. 2002).
NTHL1 (hNTH1; endonuclease III-like protein 1) acts as a DNA glycosylase to cleave cytosine glycol (5,6-dihydroxycytosine), a product of cytosine oxidation, from the DNA sugar-phosphate backbone, creating an apurinic/apyrimidinic (AP) site (Dizdaroglu et al. 1999). After the AP site is created, NTHL1 can act as a beta lyase to cleave the DNA strand 5' to the AP site (Ikeda et al. 1998).
NTHL1 (hNTH1; endonuclease III-like protein 1) acts as a DNA glycosylase to cleave 5,6-dihydrouracil, formed by deamination of cytosine with partial saturation of the pyrimidine ring (Dizdaroglu et al. 1993), from the DNA sugar-phosphate backbone, and leaves an apurinic/apyrimidinic (AP) site. After the AP site is created, NTHL1 acts as a beta lyase to cleave the DNA strand 5' to the AP site (Ikeda et al. 1998).
NTHL1 (hNTH1; endonuclease III-like protein 1) acts as a FapyA DNA glycosylase to cleave FapyA (4,6-diamino-5-formamidopyrimidine), an imidazole ring-opened adenine derivative formed during oxidative stress (Evans et al. 2004), from the DNA sugar phosphate backbone, creating an apurinic/apyrimidinic (AP) site (Luna et al. 2000, Hu et al. 2005). After the AP site is created, NTHL1 can act as a beta lyase to cleave the DNA strand 5' to the AP site (Ikeda et al. 1998).
MBD4 (MED1; methyl-CpG-binding domain protein 4) cleaves uracil mispaired with guanine at non-methylated CpG islands, leaving an apurinic/apyrimidinic (AP) DNA site (Petronzelli et al. 2000).
MBD4 (MED1; methyl-CpG-binding domain protein 4) cleaves thymine mispaired with guanine at CpG islands, which is a consequence of the oxidative deamination of 5-methylcytosine (Petronzelli et al. 2000). The MBD4 catalytic site is located at the C-terminus (Wu et al. 2003). MBD4 may be involved in the maintenance of genomic stability and active DNA demethylation.
TDG, a G/T mismatch-specific DNA glycosylase, cleaves ethenocytosine mispaired with guanine, leaving an apurinic/apyrimidinic (AP) site in the DNA (Hang et al. 1998).
OGG1 is an N-glycosylase and DNA lyase that recognizes oxidative DNA damage in the form of 8-oxoguanine (8oxoG). 8oxoG forms at a high frequency in the DNA of aerobic organisms. As 8oxoG has a preference for mispairing with adenine, it is one of the underlying causes of G:C -> T:A transversions, the type of mutation frequently found in cancer (Aburatani et al. 1997, Rosenquist et al. 1997, Roldan-Arjona et al. 1997, Radicella et al. 1997, Bjoras et al. 1997, Bruner et al. 2000).
Besides recognizing 8-oxoguanine in the oxidation-damaged DNA, OGG1 also recognizes guanine derivative FapyG (Hu et al. 2005). FapyG stands for 2,6-diamino-4-hydroxy-5-formamidopyrimidine, a ring-opened lesion that forms when hydroxyl radicals attack guanine, followed by one-electron reduction of the hydroxyl adduct radicals (Evans et al. 2004).
MUTYH (MYH), an adenine DNA glycosylase, was cloned as the human homolog of E.coli DNA repair gene mutY (Slupska et al. 1996). MUTYH recognizes adenines and 2-hydroxyadenines on the newly synthesized DNA strand mispaired with guanines or 8-oxoguanines on the template strand (Ohtsubo et al. 2000, Boldogh et al. 2001).
MPG, a 3-methyladenine DNA glycosylase, recognizes alkylation damage of DNA in the form of 3-methyladenine (Samson et al. 1991, Vickers et al. 1993, O'Connor 1993, Lau et al. 1998).
MPG, a 3-methyladenine DNA glycosylase, recognizes alkylation damage of DNA in the form of 1,N6-ethenoadenine (Dosanjh et al. 1994, Saparbaev et al. 1995).
OGG1 acts as an N-glycosylase and a DNA beta-lyase to excise 8-oxoguanine (8oxoG) from dsDNA, creating an apurinic/apyrimidinic (AP) site, and to nick the DNA sugar-phosphate backbone 5' to the AP site, creating a single strand break (SSB) (Aburatani et al. 1997, Rosenquist et al. 1997, Roldan-Arjona et al. 1997, Radicella et al. 1997, Bjoras et al. 1997, Bruner et al. 2000).
OGG1 acts as an N-glycosylase and a DNA beta-lyase to excise 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), a one electron reduction product of guanine, from the DNA and to nickk the sugar-phosphate backbone 5' to the created apurinic/apyrimidinic (AP) site (Hu et al. 2005).
MUTYH (MYH) functions as an adenine DNA glycosylase and removes adenines and 2-hydroxyadenines on the newly synthesized DNA strand mispaired with guanines or 8-oxoguanines on the template strand (Ohtsubo et al. 2000, Boldogh et al. 2001). Under physiological conditions, the preferred substrate for both MUTYH isoforms, MUTYH-3 (alpha-3) and MUTYH-6 (gamma-3) is adenine mispaired with 8-oxoguanine (OGUA:Ade) (Shinmura et al. 2000).
MPG, a 3-methyladenine DNA glycosylase, removes the alkylated DNA base 3-methyladenine (Samson et al. 1991, Vickers et al. 1993, O'Connor 1993). MPG slides along DNA and scans for alkylated bases by inducing cooperative distortions of the double helix that expose nucleotides to the active site of the enzyme (Lau et al. 1998). MPG interacts with both alkylated and unmodified nucleotides and, at a low rate, cleaves unmodified bases (Berdal et al. 1998).
NEIL1 (endonuclease 8-like protein 1), an enzyme with dual DNA glycosylase and beta/delta lyase activity, recognizes and binds DNA damage in the form of dihydrouracil (DHU) (Hazra et al. 2002). 5,6-dihydrouracil is a form of DNA damage produced by ionizing radiation under anoxic conditions, so that cytosine is deaminated and C5-C6 double bond in the pyrimidine ring is saturated with hydrogen. 5,6-dihydrouracil mispairs with adenine, leading to G:C -> A:T transitions (Dizdaroglu et al. 1993).
NEIL1 (endonuclease 8-like protein 1) recognizes guanine derivative FapyG (Hazra et al. 2002). FapyG stands for 2,6-diamino-4-hydroxy-5-formamidopyrimidine, a ring-opened lesion that forms when hydroxyl radicals attack guanine, followed by one-electron reduction of the hydroxyl adduct radicals (Evans et al. 2004).
NEIL1 (endonuclease 8-like protein 1) recognizes and binds 4,6-diamino-5-formamidopyrimidine (FapyA), an imidazole ring-opened adenine derivative (Hazra et al. 2002). FapyA is formed during oxidative stress when hydroxyl radicals attack adenine, followed by one-electron reduction of the hydroxyl adduct radicals (Evans et al. 2004).
NEIL2 (endonuclease 8-like protein 2), an enzyme with a dual DNA glysocylase and beta/delta lyase activity, recognizes 5-hydroxyuracil (5-OHU) created by DNA damaging oxidation of cytosine (Hazra et al. 2002).
NEIL3, a DNA glycosylase of the NEIL family, recognizes and binds to damaged telomeric DNA containing 5-guanidinohydantoin (Gh). Binding of NEIL3 to telomeric DNA is facilitated by interaction of NEIL3 with TRF1, a component of the telomeric shelterin complex (Zhou et al. 2017).
NEIL3 cleaves oxidatively damaged guanine, in the form of 5-guanidinohydantoin (Gh), from telomeric DNA, creating and abasic (AP) site. NEIL3 expression is highest in late S phase, overlapping with telomeric DNA synthesis. NEIL3 localization at telomeres increases in response to oxidative stress. NEIL3 knockdown results in telomere dysfunction, which can lead to metaphase arrest or increased DNA bridging during anaphase. NEIL3 interacts with enzymes involved in PCNA-dependent long patch base excision repair (BER) of AP sites, but the exact mechanism of NEIL3-mediated long patch BER of damaged telomeric DNA has not been elucidated (Zhou et al. 2017). Besides telomeres, NEIL3 is also enriched in replisomes in the S phase of the cell cycle, co-localizing with RPA in replication foci (Bjoras et al. 2017). Expression of the NEIL3 gene in the S phase may be induced by E2F transcription factors, as the NEIL3 promoter contains E2F binding elements (Neurauter et al. 2012).
NEIL3 recognizes and binds to oxidatively damaged guanine base in the form of 5-guanidinohydantoin (Gh), with a preference for single-strand DNA (ssDNA) over double-strand DNA (dsDNA) (Krokeide et al. 2013). NEIL3 also cleaves Gh in G4 quadruplex DNA formed by telomere sequences (Zhou et al. 2013).
NEIL3 recognizes DNA damage in the form of guanine oxidized to spiroiminodihydantoin (Sp), with a preference for single-strand DNA (ssDNA) over double-strand DNA (dsDNA) (Liu et al. 2012, Krokeide et al. 2013).
NEIL3 recognizes oxidatively damaged thymine in the form of thymine glycol (Tg) in DNA, with a preference for single strand DNA (ssDNA) over double-strand DNA (dsDNA) (Liu et al. 2012, Zhou et al. 2013).
NEIL3 cleaves oxidatively damaged guanin in the form of 5-guanidinohydantoin with a preference for single-strand DNA (ssDNA) over double-strand DNA (dsDNA), producing and abasic site (AP site) (Liu et al. 2010, Krokeide et al. 2013).
NEIL3 cleaves oxidatively damaged guanine in the form of spiroiminodihydantoin (Sp) form telomeric DNA, leaving an abasic (AP) site (Zhou et al. 2013).
NEIL3 cleaves oxidatively damaged guanine in the form of spiroiminodihydantoin (Sp) with a preference for single-strand DNA (ssDNA) over double-strand DNA (dsDNA), producing an abasic (AP) site (Krokeide et al. 2013). The preference of NEIL3 for ssDNA was structurally explained using mouse Neil3 (Liu et al. 2013).
NEIL3 cleaves oxidatively damaged thymine in the form of thymine glycol (Tg) from telomeric DNA, producing an abasic (AP) site (Zhou et al. 2013). NEIL3 prefers Tg damages in telomeric DNA over random sequences.
NEIL3 cleaves oxidatively damaged thymine in the form of thymine glycol (Tg) with a preference for single strand DNA (ssDNA) over double strand DNA (dsDNA), producing an abasic (AP) site (Liu et al. 2010, Zhou et al. 2013).
NEIL1 localizes to the nucleus. The nuclear localization signal (NLS) is predicted to be located at positions 359-378 of NEIL1, but the mechanism of NEIL1 translocation from the cytosol to the nucleus has not been elucidated (Shinmura et al. 2015).
NEIL3 can resolve interstrand crosslinks (ICLs) in replicating DNA, induced by intercalating DNA damaging agent psoralen, which cross links thymine bases from two replicated double strand DNAs (dsDNAs). NEIL3-mediated cleavage of psoralen-induced ICLs results in one dsDNA molecule with an abasic site (AP site) and one dsDNA molecule with a thymine-psoralen adduct. NEIL3-mediated resolution of ICLs is independent of the Fanconia anemia (FA) pathway and was demonstrated for both Xenopus (Semlow et al. 2016) and human (Martin et al. 2017) NEIL3.
Based on studies in Xenopus, NEIL3 is able to resolve abasic site-induced interstrand crosslinks (AP-ICLs), that form when an aldehyde group of the AP site reacts with the amine of a nucleic acid base, usually adenine, on the opposite strand. NEIL3-mediated unhooking of AP-ICLs is independent of the Fanconi anemia (FA) pathway (Semlow et al. 2016).
OGG1 splicing isoform beta contains a mitochondrial targeting sequence at the N-terminus and lacks the C-terminal nuclear localization signal. OGG1beta localizes to mitochondria (Nishioka et al. 1999).
OGG1 S326C is a frequent genetic polymorphism, present in more than 20% of people of European and Asian descent (Janssen et al. 2001, Moritz et al. 2014). On its own, substitution of serine with cysteine at position 326 does not affect the catalytic activity of OGG1 (Dherin et al. 1999, Janssen et al. 2001, Moritz et al. 2014). However, under oxidative stress, OGG1 S326C variant is more susceptible to oxidation or nitrosation than the wild type enzyme (Moritz et al. 2014), which diminishes catalytic activity and leads to accumulation of genomic 8-oxoguanine (8oxoG) (Yamane et al. 2004, Moritz et al. 2014) under conditions of oxidative stress (Kershaw and Hodges 2012). This may be due to decreased specificity of OGG1 S326C for 8oxoG and FapyG (Dherin et al. 1999). The frequency of OGG1 S326C allele is increased in NSCLC patients and the level of 8-oxodG is higher in lung tissue and leukocytes of these patients (Janik et al. 2011). OGG1 S326C variant is associated with an increased breast cancer risk (Ali et al. 2015).
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Besides telomeres, NEIL3 is also enriched in replisomes in the S phase of the cell cycle, co-localizing with RPA in replication foci (Bjoras et al. 2017).
Expression of the NEIL3 gene in the S phase may be induced by E2F transcription factors, as the NEIL3 promoter contains E2F binding elements (Neurauter et al. 2012).
The frequency of OGG1 S326C allele is increased in NSCLC patients and the level of 8-oxodG is higher in lung tissue and leukocytes of these patients (Janik et al. 2011). OGG1 S326C variant is associated with an increased breast cancer risk (Ali et al. 2015).