Nucleotide excision repair in xeroderma pigmentosum (Homo sapiens)

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52221282216162819, 20263214, 7Recognition of UV-damangedDNA blocks RNA polymerase and serves as a damage recognitioin signal 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).DNA lesionEarly chromatin remodelingExcised nucleotidesDNA damage signalingDNA unwinding by XPB and XPD helicasesXPC complexStep 1 - Recognition of damaged DNATranscription factor II H (TFIIH)5' 3'orStep 4 - gap-filling DNA synthesis and ligationUVRTranscription-coupled repairTCR-initiation complexUV-damaged DNA Legend:UV - RadiationDNAMutated XP geneNucleotide lesionStimulation UbiquitylationUV-DDBInhibition of UV-DDB when no UV-damage is present.With UV damage, inhibition is lifted RPA122217HMGN1SLX4RAD18LIG1LIG3p52/GTF2H4TTDA/GTF2H5TFIISRPA1CSN (COP9)POLKUSP7XRCC1POLHHistone H2ACSBRAD23BCHD1L (ALC1)Histone H3RPA3RPA2XRCC1Histone H4XPAPARP1POLD1XPAUVSSASLX4IPXAB2ERCC6 (CSB)RNA polymerase II10182723102112, 157, 8, 156RBX1CUL4ACUL4BERCC8 (CSA)DDB1CDK7 MNAT1CCNHXPD/ERCC2XPB/ERCC3p62/GTF2H1p44/GTF2H2p34 /GTF2H3XPF/ERCC1XPG/ERCC4Step 3 - Incision and excision14POLD2POLD3POLD4POLEPOLE2POLE3POLE4PCNARFC1RFC2RFC3RFC4RFC5LigationGlobal genome repairXPE complexRBX1CUL4A13CUL4BXPE (DDB2)7DDB1XPCRAD23A (?)CETN2 (Centrin 2)25RPARPA3RPA2RPA1in non-replicating cellsin replicating cellsCSN (COP9)2XPD/ERCC2XPB/ERCC3RPARPA3RPA2RPA1Step 2 - DNA binding and unwinding3


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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  1. Zhang H, Chen Z, Ye Y, Ye Z, Cao D, Xiong Y, Srivastava M, Feng X, Tang M, Wang C, Tainer JA, Chen J; ''SLX4IP acts with SLX4 and XPF-ERCC1 to promote interstrand crosslink repair.''; Nucleic Acids Res, 2019 PubMed Europe PMC Scholia
  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
  14. Huttner D, Ulrich HD; ''Cooperation of replication protein A with the ubiquitin ligase Rad18 in DNA damage bypass.''; Cell Cycle, 2008 PubMed Europe PMC Scholia
  15. Vermeulen W, Fousteri M; ''Mammalian transcription-coupled excision repair.''; Cold Spring Harb Perspect Biol, 2013 PubMed Europe PMC Scholia
  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
  17. Rapić-Otrin V, McLenigan MP, Bisi DC, Gonzalez M, Levine AS; ''Sequential binding of UV DNA damage binding factor and degradation of the p48 subunit as early events after UV irradiation.''; Nucleic Acids Res, 2002 PubMed Europe PMC Scholia
  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
  19. Tian F, Sharma S, Zou J, Lin SY, Wang B, Rezvani K, Wang H, Parvin JD, Ludwig T, Canman CE, Zhang D; ''BRCA1 promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade.''; Proc Natl Acad Sci U S A, 2013 PubMed Europe PMC Scholia
  20. Thakar T, Leung W, Nicolae CM, Clements KE, Shen B, Bielinsky AK, Moldovan GL; ''Ubiquitinated-PCNA protects replication forks from DNA2-mediated degradation by regulating Okazaki fragment maturation and chromatin assembly.''; Nat Commun, 2020 PubMed Europe PMC Scholia
  21. Fadda E; ''Role of the XPA protein in the NER pathway: A perspective on the function of structural disorder in macromolecular assembly.''; Comput Struct Biotechnol J, 2016 PubMed Europe PMC Scholia
  22. Kumar N, Raja S, Van Houten B; ''The involvement of nucleotide excision repair proteins in the removal of oxidative DNA damage.''; Nucleic Acids Res, 2020 PubMed Europe PMC Scholia
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  26. 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.''; Cell, 2011 PubMed Europe PMC Scholia
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  28. 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.''; Mol Cell, 2010 PubMed Europe PMC Scholia
  29. Miao F, Bouziane M, Dammann R, Masutani C, Hanaoka F, Pfeifer G, O'Connor TR; ''3-Methyladenine-DNA glycosylase (MPG protein) interacts with human RAD23 proteins.''; J Biol Chem, 2000 PubMed Europe PMC Scholia
  30. Majka J, Burgers PM; ''The PCNA-RFC families of DNA clamps and clamp loaders.''; Prog Nucleic Acid Res Mol Biol, 2004 PubMed Europe PMC Scholia


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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


View all...
NameTypeDatabase referenceComment
BRCA1GeneProductENSG00000012048 (Ensembl)
CCNHGeneProductENSG00000134480 (Ensembl)
CDK7 GeneProductENSG00000134058 (Ensembl) This subcomplex dissociates after XPA binds
CETN2 (Centrin 2)GeneProductENSG00000147400 (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)
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)
RAD23A (?)GeneProductENSG00000179262 (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)
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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