DNA Damage Bypass (Homo sapiens)

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In addition to various processes for removing lesions from the DNA, cells have developed specific mechanisms for tolerating unrepaired damage during the replication of the genome. These mechanisms are collectively called DNA damage bypass pathways. The Y family of DNA polymerases plays a key role in DNA damage bypass.

Y family DNA polymerases, REV1, POLH (DNA polymerase eta), POLK (DNA polymerase kappa) and POLI (DNA polymerase iota), as well as the DNA polymerase zeta (POLZ) complex composed of REV3L and MAD2L2, are able to carry out translesion DNA synthesis (TLS) or replicative bypass of damaged bases opposite to template lesions that arrest high fidelity, highly processive replicative DNA polymerase complexes delta (POLD) and epsilon (POLE). REV1, POLH, POLK, POLI and POLZ lack 3'->5' exonuclease activity and exhibit low fidelity and weak processivity. The best established TLS mechanisms are annotated here. TLS details that require substantial experimental clarification have been omitted. For recent and past reviews of this topic, please refer to Lehmann 2000, Friedberg et al. 2001, Zhu and Zhang 2003, Takata and Wood 2009, Ulrich 2011, Saugar et al. 2014. Source:Reactome.</div>

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53. Friedberg EC, Fischhaber PL, Kisker C.; ''Error-prone DNA polymerases: novel structures and the benefits of infidelity.''; PubMed Europe PMC Scholia
54. Giannakopoulos NV, Luo JK, Papov V, Zou W, Lenschow DJ, Jacobs BS, Borden EC, Li J, Virgin HW, Zhang DE.; ''Proteomic identification of proteins conjugated to ISG15 in mouse and human cells.''; PubMed Europe PMC Scholia
55. Everson RB, Randerath E, Santella RM, Cefalo RC, Avitts TA, Randerath K.; ''Detection of smoking-related covalent DNA adducts in human placenta.''; PubMed Europe PMC Scholia
56. Murakumo Y, Ogura Y, Ishii H, Numata S, Ichihara M, Croce CM, Fishel R, Takahashi M.; ''Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7.''; PubMed Europe PMC Scholia
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60. Takata K, Wood RD.; ''Bypass specialists operate together.''; PubMed Europe PMC Scholia
61. Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R, D'Andrea AD.; ''Regulation of monoubiquitinated PCNA by DUB autocleavage.''; PubMed Europe PMC Scholia
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75. Nair DT, Johnson RE, Prakash L, Prakash S, Aggarwal AK.; ''Hoogsteen base pair formation promotes synthesis opposite the 1,N6-ethenodeoxyadenosine lesion by human DNA polymerase iota.''; PubMed Europe PMC Scholia
76. Kikuchi S, Hara K, Shimizu T, Sato M, Hashimoto H.; ''Structural basis of recruitment of DNA polymerase ζ by interaction between REV1 and REV7 proteins.''; PubMed Europe PMC Scholia
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Compare	Revision	Action	Time	User	Comment
	115091	view	17:04, 25 January 2021	ReactomeTeam	Reactome version 75
	113533	view	12:01, 2 November 2020	ReactomeTeam	Reactome version 74
	112731	view	16:13, 9 October 2020	ReactomeTeam	Reactome version 73
	101647	view	11:51, 1 November 2018	ReactomeTeam	reactome version 66
	101183	view	21:39, 31 October 2018	ReactomeTeam	reactome version 65
	100709	view	20:11, 31 October 2018	ReactomeTeam	reactome version 64
	100259	view	16:56, 31 October 2018	ReactomeTeam	reactome version 63
	99812	view	15:20, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
	99356	view	12:48, 31 October 2018	ReactomeTeam	reactome version 62
	93950	view	13:47, 16 August 2017	ReactomeTeam	reactome version 61
	93543	view	11:26, 9 August 2017	ReactomeTeam	reactome version 61
	86644	view	09:23, 11 July 2016	ReactomeTeam	reactome version 56
	83335	view	10:49, 18 November 2015	ReactomeTeam	Version54
	81489	view	13:01, 21 August 2015	ReactomeTeam	Version53
	76966	view	08:24, 17 July 2014	ReactomeTeam	Fixed remaining interactions
	76671	view	12:03, 16 July 2014	ReactomeTeam	Fixed remaining interactions
	76000	view	10:05, 11 June 2014	ReactomeTeam	Re-fixing comment source
	75703	view	11:04, 10 June 2014	ReactomeTeam	Reactome 48 Update
	75059	view	13:57, 8 May 2014	Anwesha	Fixing comment source for displaying WikiPathways description
	74703	view	08:46, 30 April 2014	ReactomeTeam	Reactome46
	45195	view	10:04, 7 October 2011	MartijnVanIersel	Ontology Term : 'DNA repair pathway' added !
	42026	view	21:51, 4 March 2011	MaintBot	Automatic update
	39829	view	05:51, 21 January 2011	MaintBot	New pathway

External references

DataNodes

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Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Base Excision Repair	Pathway	R-HSA-73884 (Reactome)	Of the three major pathways involved in the repair of nucleotide damage in DNA, base excision repair (BER) involves the greatest number of individual enzymatic activities. This is the consequence of the numerous individual glycosylases, each of which recognizes and removes a specific modified base(s) from DNA. BER is responsible for the repair of the most prevalent types of DNA lesions, oxidatively damaged DNA bases, which arise as a consequence of reactive oxygen species generated by normal mitochondrial metabolism or by oxidative free radicals resulting from ionizing radiation, lipid peroxidation or activated phagocytic cells. BER is a two-step process initiated by one of the DNA glycosylases that recognizes a specific modified base(s) and removes that base through the catalytic cleavage of the glycosydic bond, leaving an abasic site without disruption of the phosphate-sugar DNA backbone. Subsequently, abasic sites are resolved by a series of enzymes that cleave the backbone, insert the replacement residue(s), and ligate the DNA strand. BER may occur by either a single-nucleotide replacement pathway or a multiple-nucleotide patch replacement pathway, depending on the structure of the terminal sugar phosphate residue. The glycosylases found in human cells recognize "foreign adducts" and not standard functional modifications such as DNA methylation (Lindahl and Wood 1999, Sokhansanj et al. 2002).
CUL4A	Protein	Q13619 (Uniprot-TrEMBL)
CUL4B	Protein	Q13620 (Uniprot-TrEMBL)
DDB1	Protein	Q16531 (Uniprot-TrEMBL)
DNA polymerase Y:MonoUb:K164,ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template	Complex	R-HSA-5653761 (Reactome)
DNA polymerase Y:MonoUb:K164-PCNA:RPA:RFC:TLS-DNA Template	Complex	R-HSA-5653660 (Reactome)
DNA polymerase Y		R-HSA-5653659 (Reactome)
DTL	Protein	Q9NZJ0 (Uniprot-TrEMBL)
Damaged DNA Template		R-HSA-5651987 (Reactome)
Damaged dsDNA		R-HSA-5652135 (Reactome)
H2O	Metabolite	CHEBI:15377 (ChEBI)
ISG-K164,ISG-K168-PCNA	Protein	P12004 (Uniprot-TrEMBL)
ISG15	Protein	P05161 (Uniprot-TrEMBL)
ISG15:UBA7	Complex	R-HSA-5653757 (Reactome)
ISG15	Protein	P05161 (Uniprot-TrEMBL)
ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template	Complex	R-HSA-5653772 (Reactome)
K164-PCNA-G157-ISG15	Protein	P05161 (Uniprot-TrEMBL)
K168-PCNA-G157-ISG15	Protein	P05161 (Uniprot-TrEMBL)
KIAA0101	Protein	Q15004 (Uniprot-TrEMBL)
MAD2L2	Protein	Q9UI95 (Uniprot-TrEMBL)
MAD2L2	Protein	Q9UI95 (Uniprot-TrEMBL)
Mg2+	Metabolite	CHEBI:18420 (ChEBI)
Mn2+	Metabolite	CHEBI:29035 (ChEBI)
MonoUb-K15,K24-KIAA0101	Protein	Q15004 (Uniprot-TrEMBL)
MonoUb-K164-PCNA	Protein	P12004 (Uniprot-TrEMBL)
MonoUb-K682,K686,K694,K709-POLH	Protein	Q9Y253 (Uniprot-TrEMBL)
MonoUb:K15,K24-KIAA0101	Complex	R-HSA-5655177 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:AP-DNA Template	Complex	R-HSA-5652039 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:Damaged DNA Template	Complex	R-HSA-5652003 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:EtAD-DNA Template,Gamma-HOPdG-DNA Template	Complex	R-HSA-5656114 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:TT-CPD-DNA Template	Complex	R-HSA-5653905 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:Tg-DNA Template,OGUA-DNA Template,BPDE-G-DNA Template	Complex	R-HSA-5655850 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:USP1:ZBTB32:Damaged DNA Template	Complex	R-HSA-5655479 (Reactome)
MonoUb:K682,K686,K694,K709-POLH	Complex	R-HSA-5655156 (Reactome)
NPLOC4	Protein	Q8TAT6 (Uniprot-TrEMBL)
NPLOC4:UFD1L:VCP:SPRTN:POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template	Complex	R-HSA-5654991 (Reactome)
NPLOC4:UFD1L:VCP	Complex	R-HSA-5654992 (Reactome)
NPLOC4:UFD1L:VPC:SPRTN:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-Template DNA	Complex	R-HSA-5654988 (Reactome)
PCNA	Protein	P12004 (Uniprot-TrEMBL)
PCNA:POLD,POLE:RPA:RFC:Damaged DNA Template	Complex	R-HSA-5651995 (Reactome)
PCNA:POLD,POLE:RPA:RFC:TLS-DNA Template	Complex	R-HSA-5653837 (Reactome)
PCNA:POLD,POLE:RPA:RFC	Complex	R-HSA-5651799 (Reactome)
PCNA:RPA:RFC:Damaged DNA Template	Complex	R-HSA-5655467 (Reactome)
PCNA:RPA:RFC:TLS-DNA Template	Complex	R-HSA-5653782 (Reactome)
POLD,POLE		R-HSA-5651800 (Reactome)
POLH	Protein	Q9Y253 (Uniprot-TrEMBL)
POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA)-DNA Template	Complex	R-HSA-110290 (Reactome)
POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template	Complex	R-HSA-5654981 (Reactome)
POLH:MonoUb:K164-PCNA:RPA:RFC:TT-CPD-DNA Template	Complex	R-HSA-110288 (Reactome)
POLH:RCHY1	Complex	R-HSA-5655139 (Reactome)
POLH	Protein	Q9Y253 (Uniprot-TrEMBL)
POLI	Protein	Q9UNA4 (Uniprot-TrEMBL)
POLI:Mg2+	Complex	R-HSA-5656093 (Reactome)
POLI:MonoUb:K164-PCNA:RPA:RFC:(EtAD:T-mispaireddNMPs)-DNA Template,(Gamma-HOPdG:C-mispaireddNMPs)-DNA Template	Complex	R-HSA-5656156 (Reactome)
POLI:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:(EtAD:T)-DNA Template,(Gamma-HOPdG:C)-DNA Template	Complex	R-HSA-5656146 (Reactome)
POLI:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:EtAD-DNA Template,Gamma-HOPdG-DNA Template	Complex	R-HSA-5656097 (Reactome)
POLK	Protein	Q9UBT6 (Uniprot-TrEMBL)
POLK:Mg2+,Mn2+	Complex	R-HSA-5655492 (Reactome)
POLK:MonoUb:K164-PCNA:RPA:RFC:(Tg:A-mispaireddNMPs)-DNA Template,(OGUA:A-mispaireddNMPs)-DNA Template,(BPDE-G:C-mispaireddNMPs)-DNA Template	Complex	R-HSA-5655961 (Reactome)
POLK:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:(Tg:A)-DNA Template,(OGUA:A)-DNA Template,(BPDE-G:C)-DNA Template	Complex	R-HSA-5655912 (Reactome)
POLK:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:Tg-DNA Template,OGUA-DNA Template,BPDE-G-DNA Template	Complex	R-HSA-5655852 (Reactome)
POLZ:REV1:MonoUb:K164-PCNA:RPA:RFC:(AP:Cyt)-DNA Template	Complex	R-HSA-5652152 (Reactome)
POLZ	Complex	R-HSA-110279 (Reactome)
PPi	Metabolite	CHEBI:29888 (ChEBI)
RAD18	Protein	Q9NS91 (Uniprot-TrEMBL)
RAD18:UBE2B,RBX1:CUL4:DDB1:DTL:PCNA:POLD,POLE:RPA:RFC:Damaged DNA Template	Complex	R-HSA-5651985 (Reactome)
RAD18:UBE2B,RBX1:CUL4:DDB1:DTL		R-HSA-5655459 (Reactome)
RBX1	Protein	P62877 (Uniprot-TrEMBL)
RCHY1	Protein	Q96PM5 (Uniprot-TrEMBL)
RCHY1	Protein	Q96PM5 (Uniprot-TrEMBL)
REV1	Protein	Q9UBZ9 (Uniprot-TrEMBL)
REV1:MonoUb:K164-PCNA:RPA:RFC:(AP:Cyt)-DNA Template	Complex	R-HSA-110285 (Reactome)
REV1:MonoUb:K164-PCNA:RPA:RFC:(AP:Cyt-mispairedPolydNMP)-DNA Template	Complex	R-HSA-5652153 (Reactome)
REV1:MonoUb:K164-PCNA:RPA:RFC:AP-DNA Template	Complex	R-HSA-110283 (Reactome)
REV1	Protein	Q9UBZ9 (Uniprot-TrEMBL)
REV3L	Protein	O60673 (Uniprot-TrEMBL)
REV3L	Protein	O60673 (Uniprot-TrEMBL)
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)
RPA1	Protein	P27694 (Uniprot-TrEMBL)
RPA2	Protein	P15927 (Uniprot-TrEMBL)
RPA3	Protein	P35244 (Uniprot-TrEMBL)
RPS27A(1-76)	Protein	P62979 (Uniprot-TrEMBL)
SPRTN	Protein	Q9H040 (Uniprot-TrEMBL)
SPRTN:POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template	Complex	R-HSA-5654984 (Reactome)
SPRTN	Protein	Q9H040 (Uniprot-TrEMBL)
TRIM25	Protein	Q14258 (Uniprot-TrEMBL)
UBA52(1-76)	Protein	P62987 (Uniprot-TrEMBL)
UBA7	Protein	P41226 (Uniprot-TrEMBL)
UBA7	Protein	P41226 (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)
UBE2B	Protein	P63146 (Uniprot-TrEMBL)
UBE2L6	Protein	O14933 (Uniprot-TrEMBL)
UBE2L6:TRIM25:DNA polymerase Y:MonoUb:K164-PCNA:RPA:RFC:TLS-DNA Template	Complex	R-HSA-5653760 (Reactome)
UBE2L6:TRIM25	Complex	R-HSA-5653664 (Reactome)
UFD1L	Protein	Q92890 (Uniprot-TrEMBL)
USP1	Protein	O94782 (Uniprot-TrEMBL)
USP1(1-671)	Protein	O94782 (Uniprot-TrEMBL)
USP1(672-785)	Protein	O94782 (Uniprot-TrEMBL)
USP10	Protein	Q14694 (Uniprot-TrEMBL)
USP10:DNA polymerase Y:MonoUb:K164,ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template	Complex	R-HSA-5653773 (Reactome)
USP10	Protein	Q14694 (Uniprot-TrEMBL)
USP1:ZBTB32	Complex	R-HSA-419551 (Reactome)
USP43	Protein	Q70EL4 (Uniprot-TrEMBL)
USP43:ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template	Complex	R-HSA-5653781 (Reactome)
USP43	Protein	Q70EL4 (Uniprot-TrEMBL)
VCP	Protein	P55072 (Uniprot-TrEMBL)
ZBTB32	Protein	Q9Y2Y4 (Uniprot-TrEMBL)
ZBTB32	Protein	Q9Y2Y4 (Uniprot-TrEMBL)
dATP	Metabolite	CHEBI:16284 (ChEBI)
dCTP	Metabolite	CHEBI:16311 (ChEBI)
dNTP	Metabolite	CHEBI:16516 (ChEBI)
ubiquitin		R-HSA-68524 (Reactome)

Annotated Interactions

View all...

Source	Target	Type	Database reference	Comment
	ADP	Arrow	R-HSA-5654989 (Reactome)
ATP			R-HSA-5654989 (Reactome)
	DNA polymerase Y:MonoUb:K164,ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template	Arrow	R-HSA-5653754 (Reactome)
DNA polymerase Y:MonoUb:K164,ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template			R-HSA-5653766 (Reactome)
DNA polymerase Y:MonoUb:K164-PCNA:RPA:RFC:TLS-DNA Template			R-HSA-5653756 (Reactome)
	DNA polymerase Y	Arrow	R-HSA-5653770 (Reactome)
	Damaged DNA Template	Arrow	R-HSA-5652137 (Reactome)
Damaged DNA Template			R-HSA-5651992 (Reactome)
	Damaged dsDNA	Arrow	R-HSA-5653840 (Reactome)
Damaged dsDNA			R-HSA-5652137 (Reactome)
H2O			R-HSA-5653770 (Reactome)
H2O			R-HSA-5653786 (Reactome)
ISG15:UBA7			R-HSA-5653754 (Reactome)
	ISG15	Arrow	R-HSA-5653786 (Reactome)
	ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template	Arrow	R-HSA-5653770 (Reactome)
ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template			R-HSA-5653780 (Reactome)
KIAA0101			R-HSA-5655193 (Reactome)
MAD2L2			R-HSA-110322 (Reactome)
MonoUb:K15,K24-KIAA0101		Arrow	R-HSA-5653838 (Reactome)
	MonoUb:K15,K24-KIAA0101	Arrow	R-HSA-5655193 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:AP-DNA Template			R-HSA-110307 (Reactome)
	MonoUb:K164-PCNA:RPA:RFC:Damaged DNA Template	Arrow	R-HSA-5652009 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:Damaged DNA Template			R-HSA-5655481 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:EtAD-DNA Template,Gamma-HOPdG-DNA Template			R-HSA-5656105 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:TT-CPD-DNA Template			R-HSA-110316 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:Tg-DNA Template,OGUA-DNA Template,BPDE-G-DNA Template			R-HSA-5655835 (Reactome)
	MonoUb:K164-PCNA:RPA:RFC:USP1:ZBTB32:Damaged DNA Template	Arrow	R-HSA-5655481 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:USP1:ZBTB32:Damaged DNA Template			R-HSA-5655466 (Reactome)
MonoUb:K164-PCNA:RPA:RFC:USP1:ZBTB32:Damaged DNA Template		mim-catalysis	R-HSA-5655466 (Reactome)
	MonoUb:K682,K686,K694,K709-POLH	Arrow	R-HSA-5655170 (Reactome)
	NPLOC4:UFD1L:VCP:SPRTN:POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template	Arrow	R-HSA-5654985 (Reactome)
NPLOC4:UFD1L:VCP:SPRTN:POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template			R-HSA-5654989 (Reactome)
NPLOC4:UFD1L:VCP:SPRTN:POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template		mim-catalysis	R-HSA-5654989 (Reactome)
NPLOC4:UFD1L:VCP			R-HSA-5654985 (Reactome)
	NPLOC4:UFD1L:VPC:SPRTN:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-Template DNA	Arrow	R-HSA-5654989 (Reactome)
	PCNA:POLD,POLE:RPA:RFC:Damaged DNA Template	Arrow	R-HSA-5651992 (Reactome)
PCNA:POLD,POLE:RPA:RFC:Damaged DNA Template			R-HSA-5652005 (Reactome)
	PCNA:POLD,POLE:RPA:RFC:TLS-DNA Template	Arrow	R-HSA-5653838 (Reactome)
PCNA:POLD,POLE:RPA:RFC:TLS-DNA Template			R-HSA-5653840 (Reactome)
PCNA:POLD,POLE:RPA:RFC:TLS-DNA Template		mim-catalysis	R-HSA-5653840 (Reactome)
	PCNA:POLD,POLE:RPA:RFC	Arrow	R-HSA-5653840 (Reactome)
PCNA:POLD,POLE:RPA:RFC			R-HSA-5651992 (Reactome)
	PCNA:RPA:RFC:Damaged DNA Template	Arrow	R-HSA-5655466 (Reactome)
	PCNA:RPA:RFC:TLS-DNA Template	Arrow	R-HSA-5653786 (Reactome)
PCNA:RPA:RFC:TLS-DNA Template			R-HSA-5653838 (Reactome)
	POLD,POLE	Arrow	R-HSA-5652009 (Reactome)
POLD,POLE			R-HSA-5653838 (Reactome)
	POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA)-DNA Template	Arrow	R-HSA-110317 (Reactome)
POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA)-DNA Template			R-HSA-110319 (Reactome)
POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA)-DNA Template		mim-catalysis	R-HSA-110319 (Reactome)
	POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template	Arrow	R-HSA-110319 (Reactome)
POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template			R-HSA-5654986 (Reactome)
	POLH:MonoUb:K164-PCNA:RPA:RFC:TT-CPD-DNA Template	Arrow	R-HSA-110316 (Reactome)
POLH:MonoUb:K164-PCNA:RPA:RFC:TT-CPD-DNA Template			R-HSA-110317 (Reactome)
POLH:MonoUb:K164-PCNA:RPA:RFC:TT-CPD-DNA Template		mim-catalysis	R-HSA-110317 (Reactome)
	POLH:RCHY1	Arrow	R-HSA-5655142 (Reactome)
POLH:RCHY1			R-HSA-5655170 (Reactome)
POLH:RCHY1		mim-catalysis	R-HSA-5655170 (Reactome)
	POLH	Arrow	R-HSA-5654989 (Reactome)
POLH			R-HSA-110316 (Reactome)
POLH			R-HSA-5655142 (Reactome)
POLI:Mg2+			R-HSA-5656105 (Reactome)
	POLI:MonoUb:K164-PCNA:RPA:RFC:(EtAD:T-mispaireddNMPs)-DNA Template,(Gamma-HOPdG:C-mispaireddNMPs)-DNA Template	Arrow	R-HSA-5656158 (Reactome)
	POLI:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:(EtAD:T)-DNA Template,(Gamma-HOPdG:C)-DNA Template	Arrow	R-HSA-5656148 (Reactome)
POLI:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:(EtAD:T)-DNA Template,(Gamma-HOPdG:C)-DNA Template			R-HSA-5656158 (Reactome)
POLI:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:(EtAD:T)-DNA Template,(Gamma-HOPdG:C)-DNA Template		mim-catalysis	R-HSA-5656158 (Reactome)
	POLI:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:EtAD-DNA Template,Gamma-HOPdG-DNA Template	Arrow	R-HSA-5656105 (Reactome)
POLI:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:EtAD-DNA Template,Gamma-HOPdG-DNA Template			R-HSA-5656148 (Reactome)
POLI:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:EtAD-DNA Template,Gamma-HOPdG-DNA Template		mim-catalysis	R-HSA-5656148 (Reactome)
POLK:Mg2+,Mn2+			R-HSA-5655835 (Reactome)
	POLK:MonoUb:K164-PCNA:RPA:RFC:(Tg:A-mispaireddNMPs)-DNA Template,(OGUA:A-mispaireddNMPs)-DNA Template,(BPDE-G:C-mispaireddNMPs)-DNA Template	Arrow	R-HSA-5655965 (Reactome)
	POLK:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:(Tg:A)-DNA Template,(OGUA:A)-DNA Template,(BPDE-G:C)-DNA Template	Arrow	R-HSA-5655892 (Reactome)
POLK:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:(Tg:A)-DNA Template,(OGUA:A)-DNA Template,(BPDE-G:C)-DNA Template			R-HSA-5655965 (Reactome)
POLK:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:(Tg:A)-DNA Template,(OGUA:A)-DNA Template,(BPDE-G:C)-DNA Template		mim-catalysis	R-HSA-5655965 (Reactome)
	POLK:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:Tg-DNA Template,OGUA-DNA Template,BPDE-G-DNA Template	Arrow	R-HSA-5655835 (Reactome)
POLK:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:Tg-DNA Template,OGUA-DNA Template,BPDE-G-DNA Template			R-HSA-5655892 (Reactome)
POLK:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:Tg-DNA Template,OGUA-DNA Template,BPDE-G-DNA Template		mim-catalysis	R-HSA-5655892 (Reactome)
	POLZ:REV1:MonoUb:K164-PCNA:RPA:RFC:(AP:Cyt)-DNA Template	Arrow	R-HSA-5652151 (Reactome)
POLZ:REV1:MonoUb:K164-PCNA:RPA:RFC:(AP:Cyt)-DNA Template			R-HSA-110311 (Reactome)
POLZ:REV1:MonoUb:K164-PCNA:RPA:RFC:(AP:Cyt)-DNA Template		mim-catalysis	R-HSA-110311 (Reactome)
	POLZ	Arrow	R-HSA-110311 (Reactome)
	POLZ	Arrow	R-HSA-110322 (Reactome)
	POLZ	Arrow	R-HSA-5655965 (Reactome)
	POLZ	Arrow	R-HSA-5656158 (Reactome)
POLZ			R-HSA-5652151 (Reactome)
POLZ			R-HSA-5655835 (Reactome)
POLZ			R-HSA-5656105 (Reactome)
	PPi	Arrow	R-HSA-110311 (Reactome)
	PPi	Arrow	R-HSA-110317 (Reactome)
	PPi	Arrow	R-HSA-110319 (Reactome)
	PPi	Arrow	R-HSA-5653840 (Reactome)
	PPi	Arrow	R-HSA-5655892 (Reactome)
	PPi	Arrow	R-HSA-5655965 (Reactome)
	PPi	Arrow	R-HSA-5656148 (Reactome)
	PPi	Arrow	R-HSA-5656158 (Reactome)
			R-HSA-110307 (Reactome)	REV1 is a deoxycytidyl transferase that belongs to the DNA polymerase type-Y family. REV1 was cloned as the human homolog of yeast REV1. Similar to its yeast counterpart, REV1 binds damaged DNA, with the preferred substrate being DNA with an AP (abasic - apurinic/apyrimidinic) site. The mechanism for DNA damage recognition has not been elucidated (Lin et al. 1999, Gibbs et al. 2000). Besides DNA binding, REV1 has a ubiquitin binding motif in its C-terminal domain that interacts with monoubiquitinated PCNA, which enhances REV1-mediated translesion synthesis (Garg and Burgers 2005, Wood et al. 2007).
			R-HSA-110308 (Reactome)	REV1 acts as a deoxycytidyl transferase to incorporate a single dCMP opposite a damaged DNA residue. REV1 most efficiently incorporates dCMP opposite apurinic/apyrimidinic (AP, abasic) sites. REV1 enables DNA damage bypass without repair of damaged DNA bases, but its low fidelity results in a mutagenic effect (Nelson et al. 1996, Lin et al. 1999, Gibbs et al. 2000, Zhang et al. 2002).
			R-HSA-110311 (Reactome)	After REV1 inserts a nucleotide directly opposite the template lesion, translesion synthesis (TLS) is continued by DNA polymerase zeta (POLZ), a complex of REV3L and MAD2L2 (REV3 and REV7 in yeast) (Nelson et al. 1996a, Neal et al. 2010). POLZ is a poorly processive enzyme in both yeast and humans and usually incorporates less than 30 nucleotides before it dissociates from the template. In human cells, the processivity of POLZ is increased in the presence of DNA polymerase delta (POLD) subunits POLD2 and POLD3, which act as accessory subunits for POLZ (Nelson et al. 1996b, Lee et al. 2014). POLZ is error-prone, especially in the context of TLS across AP (apurinic/apyrimidinic) sites, resulting in incorporation of mispaired dNTPs, which contributes to TLS-related mutagenesis (Shachar et al. 2009, Lee et al. 2014).
			R-HSA-110316 (Reactome)	DNA polymerase eta (POLH) belongs to Y family of DNA polymerases. POLH binds PCNA monoubiquitinated at lysine K164 by the RAD18:UBE2B (RAD18:RAD6) or RBX1:CUL4:DDB1:DTL complexes in response to DNA damage. POLH C-terminus contains a conserved PCNA interaction motif, while the catalytic domain of POLH contains a conserved monoubiquitin binding motif. POLH is most efficient in recognition and repair of thymine-thymine cyclobutane pyrimidine dimers (TT-CPD) induced by UV-mediated DNA damage (Masutani et al. 2000, Kannouche et al. 2004)
			R-HSA-110317 (Reactome)	DNA polymerase eta (POLH) correctly incorporates two adenine deoxyribonucleotides (dAMPs) opposite a TT-CPD (thymine-thymine cyclobutane pyrimidine dimer) lesion. POLH can bypass other types of lesions, such as AP sites and cisplatin-induced intrastrand cross-linked gunanines, preferentially incorporating dAMPs and dGMPs opposite the lesion. While POLH is accurate in translesion synthesis (TLS) across thymine dimers, POLH has a low fidelity in TLS across other DNA damage types and when copying undamaged DNA. One of the protective mechanisms against POLH-induced mutagenesis may be that POLH cannot continue chain elongation after an incorrect nucleotide is incorporated (Matsuda et al. 2000, Masutani et al. 2000).
			R-HSA-110319 (Reactome)	After incorporating two dAMPs opposite the thymine-thymine cyclobutane pyrimidine dimer (TT-CPD), DNA polymerase eta (POLH) can continue translesion DNA synthesis (TLS). POLH preferentially incorporates dAMPs and dGMPs, and may introduce one error per every 18-380 nucleotides (dNMPs) added. POLH stalls after incorporation of a mispaired dNMP, which limits POLH- mediated mutagenesis, in addition to the subsequent polymerase switch (Matsuda et al. 2000, Masutani et al. 2000).
			R-HSA-110322 (Reactome)	REV3L (hREV3), the catalytic subunit of DNA polymerase zeta (POLZ) belonging to B family of DNA polymerases, binds the adapter protein MAD2L2 (hREV7) to form a functional POLZ complex (Murakamo et al. 2000, Murakamo et al. 2001, Hara et al. 2010).
			R-HSA-5651992 (Reactome)	The replication complex consisting of PCNA, DNA polymerase delta complex (POLD) or DNA polymerase epsilon complex (POLE), RPA and RFC complexes, encounters damaged dsDNA that cannot be used as a template by replicative DNA polymerases POLD or POLE (Hoege et al. 2002).
			R-HSA-5652005 (Reactome)	The complex of RAD18, an E3 ubiquitin ligase, and UBE2B (RAD6), an E2 ubiquitin-conjugating enzyme, binds the replication complex consisting of PCNA, DNA polymerase complex delta (POLD) or DNA polymerase complex epsilon (POLE), RPA and RFC on damaged dsDNA. RAD18 simultaneously interacts with PCNA, RPA and DNA (Hoege et al. 2002, Notenboom et al. 2007, Davies et al. 2008). The ubiquitin ligase complex RBX1:CUL4:DDB1:DTL can also bind PCNA (Terai et al. 2010).
			R-HSA-5652009 (Reactome)	The complex of RAD18, an E3 ubiquitin ligase, and UBE2B (RAD6), an E2 ubiquitin conjugating enzyme, monoubiquitinates PCNA associated with damaged DNA on lysine residue K164, using the ubiquitin residue K63 to create the covalent bond (Hoege et al. 2002). The catalytic subunit of DNA polymerase delta (POLD), POLD1, does not bind monoubiquitinated PCNA (Park et al. 2014), implying that replicative polymerases POLD and POLE (DNA polymerase epsilon complex) dissociate from PCNA monubiquitinated at K164. This is in accordance with the proposed DNA polymerase switch during translesion DNA synthesis (TLS) (Friedberg et al. 2005). DNA damage induced removal of PCNA-associated protein KIAA0101 (PAF15) through proteasome-mediated degradation facilitates switching from replicative DNA polymerases POLD and POLE to TLS polymerases (Povlsen et al. 2012). The ubiquitin ligase complex RBX1:CUL4:DDB1:DTL can also monoubiquitinate PCNA. RBX1:CUL4:DDB1:DTL is probably responsible for the basal monoubiquitination of PCNA and may contribute to the kinetics of DNA-damage induced PCNA monoubiquitination (Terai et al. 2010).
			R-HSA-5652137 (Reactome)	If a damaged double strand DNA (dsDNA) is not repaired prior to the next round of DNA replication, it provides a damaged (lesioned) DNA template that triggers mutagenic (erroneous) incorporation of nucleotides in the newly synthesized DNA strand through the process of DNA damage bypass (Friedberg et al. 2001).
			R-HSA-5652151 (Reactome)	REV1, bound to the replication complex, recruits DNA polymerase zeta (POLZ, REV3L:MAD2L2) to the damaged DNA template. REV3L does not bind REV1 directly. Instead, REV3L binding to MAD2L2 (REV7) during the formation of POLZ complex causes a conformational change in MAD2L2 that allows the C-terminal domain of MAD2L2 to bind the C-terminus of REV1 (Nelson et al. 1996, Hara et al. 2010, Kikuchi et al. 2012, Xie et al. 2012)
			R-HSA-5653754 (Reactome)	The complex of ISG15 E2 conjugating enzyme UBE2L6 (UBCH8) and ISG15 E3 conjugating enzyme TRIM25 (EFP) doubly ISGylates monoubiquitinated PCNA (MonoUb:K164-PCNA) on lysine residues K164 and K168. Note that PCNA is a homotrimer, meaning ISGylation of K164 (and K168) occurs on a different subunit than that monoubiquitinated on K164. UBA7 (UBE1L) is the ISG15 E1-activating enzyme (Park et al. 2014).
			R-HSA-5653756 (Reactome)	PCNA monoubiquitinated on lysine residue K164 (MonoUb:K164-PCNA) is bound by ISG15 E3 ligase TRIM25 (EFP) in complex with ISG15 E2 conjugating enzyme UBE2L6 (UBCH8) (Park et al. 2014).
			R-HSA-5653766 (Reactome)	Ubiquitin protease USP10 binds doubly ISGylated and monoubiquitinated PCNA (Park et al. 2014). PCNA exists as a homotrimer so that the ISGylation and monoubiquitination occur on different subunits.
			R-HSA-5653770 (Reactome)	USP10 acts as a ubiquitin protease to remove ubiquitin from lysine K164 residue of doubly ISGylated PCNA. Deubiquitination of PCNA by USP10 causes dissociation of Y family DNA damage bypass polymerases, thus ending translesion DNA synthesis (TLS) and limiting TLS-induced mutagenesis (Park et al. 2014).
			R-HSA-5653780 (Reactome)	The ubiquitin protease USP43 binds doubly ISGylated PCNA (Park et al. 2014).
			R-HSA-5653786 (Reactome)	USP43 acts as an ISG15 protease to cleave ISG15 from lysines K164 and K168 of PCNA, thus deISGylating PCNA (Park et al. 2014).
			R-HSA-5653838 (Reactome)	Once deubiquitinated and deISGylated, PCNA can again associate with the catalytic subunit POLD1 of replicative DNA polymerase delta complex (POLD), or presumably POLE of DNA polymerase epsilon complex (POLE) (Park et al. 2014). Double monoubiquitination of PCNA-associated protein KIAA0101 (PAF15) facilitates the switch from translesion DNA synthesis (TLS) polymerases to replicative DNA polymerases POLD or POLE (Povlsen et al. 2012).
			R-HSA-5653840 (Reactome)	After DNA damage is bypassed by error-prone DNA polymerases capable of translesion DNA synthesis (TLS), the replicative complex composed of PCNA, DNA polymerases delta (POLD) or epsilon (POLE), RPA and RFC, completes the replication of damaged DNA (Park et al. 2014). Replicated damaged DNA may then be repaired through base excision or another DNA repair mechanism before the next round of DNA replication.
			R-HSA-5654985 (Reactome)	SPRTN (Spartan, C1orf124, DVC1) contains a SHP box that binds the hexameric AAA-ATPase VCP (p97). SPRTN recruits VCP, in complex with VCP adaptors NPLOC4 and UFD1L, to monoubiquitinated PCNA (MonoUb:K164-PCNA) associated with POLH at DNA damage sites (Ghosal et al. 2012, Davis et al. 2012, Mosbech et al. 2012).
			R-HSA-5654986 (Reactome)	SPRTN (Spartan, C1orf124, DVC1) contains a PIP box and a UBZ domain that both participate in binding to monoubiquitinated PCNA (MonoUb:K164-PCNA), thus regulating POLH-mediated translesion DNA synthesis (TLS). The SPRTN UBZ domain may also interact with other monoubiquitinated proteins at the site of DNA damage. SPRTN can also bind RAD18 and function in a positive feedback loop to increase (or maintain) PCNA monoubiquitination (Centore et al. 2012, Ghosal et al. 2012). Endogenous SPRTN is predominantly expressed during S and G2 phases of the cell cycle, and is rapidly degraded by the APC:CDH1 complex at mitotic exit (Mosbech et al. 2012).
			R-HSA-5654989 (Reactome)	The ATP-ase activity of VCP facilitates release of POLH (DNA polymerase eta) from monoubiquitinated PCNA (MonoUb:K164-PCNA) at DNA damage sites, thus ending POLH-mediated translesion DNA synthesis (TLS) (Davis et al. 2012, Mosbech et al. 2012). Although conjugation of the ubiquitin-like protein ISG15 to PCNA has been found to terminate POLH-dependent TLS, the SPRTN:VCP complex has been implicated in serving as an alternative termination pathway (Park et al. 2014). Since VCP has been found to undergo ISGylation (Giannakopoulos et al. 2005), it remains to be determined whether SPRTN, VCP and the ISG15-conjugating system function in the same TLS-regulatory pathway or two separate pathways.
			R-HSA-5655142 (Reactome)	RCHY1 (Pirh2) is an E3 ubiquitin ligase that binds DNA polymerase eta (POLH). This interaction involves the polymerase-associated domain of POLH and the RING finger of RCHY1 (Jung et al. 2010).
			R-HSA-5655170 (Reactome)	RCHY1 (Pirh2) acts as an E3 ubiquitin ligase to monoubiquitinate POLH (DNA polymerase eta) on lysine residues K682, K686, K694 and K709 located in the NLS (nuclear localization signal) of POLH (Jung et al. 2011). The NLS sequence of POLH is located between UBZ domain and PIP box, involved in POLH binding to monoubiquitinated PCNA (MonoUb:K164-PCNA). POLH monoubiquitination masks the PCNA-interaction region, thus disabling POLH binding to MonoUb:K164-PCNA and preventing POLH-mediated translesion DNA synthesis (TLS) (Bienko et al. 2010).
			R-HSA-5655193 (Reactome)	KIAA0101 (PAF15) is a PCNA-associated protein expressed during S phase of the cell cycle, under the control of members of the E2F transcription factor family (Chang et al. 2013) and degraded at mitotic exit by the APC:CDH1 complex (Emanuele et al. 2011). KIAA0101 is monoubiquitinated on two lysine residues, K15 and K24, by an unknown ubiquitin ligase. Doubly monoubiquitinated KIAA0101 (PAF15) (MonoUb:K15,K24-KIAA0101) binds PCNA and promotes the switch from translesion DNA synthesis (TLS) polymerase, such as DNA polymerase eta (POLH), to replicative DNA polymerases delta (POLD) or epsilon (POLE). KIAA0101 monoubiquitination thus facilitates termination of TLS and coordinates DNA damage bypass events (Povlsen et al. 2012). UV-induced DNA damage causes removal of MonoUb:K15,K24-KIAA0101 by proteasome-mediated degradation, promoting the switch from replicative DNA polymerase complexes delta (POLD) or epsilon (POLE) to translesion DNA synthesis (TLS) polymerases, such as POLH (DNA polymerase eta) (Povlsen et al. 2012).
			R-HSA-5655466 (Reactome)	Deubiquitinating enzyme USP1, bound to its accessory protein ZBTB32 (UAF1), deubiquitinates PCNA (MonoUb:K164-PCNA), thus preventing excessive activation of DNA translesion synthesis (TLS) (Huang et al. 2006).
			R-HSA-5655481 (Reactome)	Ubiquitin protease complex composed of deubiquitinating enzyme USP1 and its accessory factor ZBTB32 (UAF1) binds monoubiquitinated PCNA (MonoUb:K164-PCNA) (Huang et al. 2006).
			R-HSA-5655483 (Reactome)	UV radiation, through an unknown mechanism, triggers USP1 autocleavage immediately after a conserved Gly-Gly motif. The products of USP1 autocleavage are targeted for proteasome-mediated degradation, thus preventing the activity of USP1:ZBTB32 deubiquitinase complex and allowing for monoubiquitinated PCNA to accumulate and stimulate translesion DNA synthesis (TLS) (Huang et al. 2006).
			R-HSA-5655835 (Reactome)	DNA polymerase kappa (POLK) forms a quaternary complex with REV1 and the DNA polymerase zeta (POLZ) heterodimer, composed of REV3L and MAD2L2 (REV7), at DNA damage sites (Ohashi et al. 2009, Wojtaszek et al. 2012a, Wojtaszek et al. 2012b, Xie et al. 2012). POLK simultaneously interacts with the C-terminus of REV1 through its RIR (REV1-interacting region) (Ohashi et al. 2009) and with monoubiquitinated PCNA (Haracska et al. 2002, Bi et al. 2006). POLK requires Mg2+ or Mn2+ for its activity. POLK is more catalytically active in the presence of Mn2+, but exhibits higher fidelity in the presence of Mg2+ (Pence et al. 2012)
			R-HSA-5655892 (Reactome)	DNA polymerase kappa (POLK) is the most efficient in incorporation of nucleotides opposite to oxidation derivatives of DNA bases, such as thymine glycol (Tg) and 8-oxoguanine (OGUA). POLK preferentially incorporates dAMP opposite both Tg and OGUA, resulting in error-free translesion DNA synthesis (TLS) across Tg lesions (Fischhaber et al. 2002, Yoon et al. 2010, Yoon et al. 2014) and frequent G:C -> T:A transversions at OGUA lesions (Zhang et al. 2000, Vasquez-Del Carpio et al. 2009). POLK is also efficient in TLS across bulky DNA adducts, such as the smoking-related benzo(a)pyrene diol epoxide guanine adduct (BPDE-G) (Everson et al. 1986), and it correctly incorporates dCMP opposite to BPDE-G (Zhang et al. 2000, Avkin et al. 2004, Lior-Hoffmann et al. 2012, Christov et al. 2012). POLK is incapable of TLS across thymine-thymine dimers (Ohashi et al. 2000) and shows a very low efficiency in TLS across AP sites, where it mainly causes single base deletions (-1 frameshifts) through template-primer misalignment (Ohashi et al. 2000, Wolfle et al. 2003).
			R-HSA-5655965 (Reactome)	DNA polymerase kappa (POLK) can elongate mispaired primer termini generated when an incorrect nucleotide is incorporated opposite a damaged DNA base either by POLK or by another translesion DNA synthesis (TLS) polymerase (Haracska et al. 2002, Carlson et al. 2006). POLK can processively synthesize polynucleotide chains that are usually not more than 20 nucleotides long, generating single base substitutions at a rate of 7/1000 and single base deletions at a rate of 3/1000 (Ohashi et al. 2000). POLK and POLZ can cooperate in the elongation of nucleotides inserted opposite to lesioned bases by POLK (Yoon et al. 2010, Wojtaszek et al. 2012a, Wojtaszek et al. 2012b, Xie et al. 2012, Yoon et al. 2014)
			R-HSA-5656105 (Reactome)	DNA polymerase iota (POLI) is recruited to DNA damage sites through its interaction with PCNA and REV1. POLI has a functional PIP box in the C-terminus and two ubiquitin binding motifs (UBMs). The PIP box and UBMs are responsible for POLI binding to monoubiquitinated PCNA (MonoUb:K164-PCNA) (Bienko et al. 2005, Haracska et al. 2005, Bomar et al. 2010). The interaction between POLI and the C-terminus of REV1 is evolutionarily conserved (Kosarek et al. 2003, Guo et al. 2003, Ohashi et al. 2004). Since REV1 and POLI likely cooperate in the bypass of bulky DNA lesions (Yang et al. 2003) and the DNA polymerase zeta complex (POLZ) is needed for extension of nucleotides incorporated by POLI (Johnson et al. 2000), it is plausible that POLI forms a quaternary complex with REV1 and POLZ, as shown for POLK and proposed for other Y family DNA polymerases (Xie et al. 2012).
			R-HSA-5656148 (Reactome)	DNA polymerase iota (POLI) has an active site that favours Hoogsteen base pairing instead of Watson-Crick base pairing. POLI has the highest efficiency and fidelity in incorporating dTTP opposite to a template adenine (A). The active site of POLI causes the template A to rotate about its glycosidic bond and acquire a syn conformation. The hydrogen bonds are then established between the Hoogsteen edge of the template A in syn conformation (N7 and N6) and the Watson-Crick edge of dTMP (N3 and O4), which remains in anti conformation. POLI shows lower efficiency in incorporating dCTP opposite the template guanine (G) (Nair et al. 2004). Hoogsteen base pairing and rotation of template purines from anti to syn conformation serves as a mechanism to displace adducts on template G or template A that interfere with DNA replication, as is the case with gamma-hydroxy-1,N2-propano-2'deoxyguanosine (gamma-HOPdG), or to allow base pairing of damaged purines with a disrupted Watson-Crick edge but an intact Hoogsteen edge, as is the case with 1,N6-ethenodeoxyadenosine (EtAD) (Nair et al. 2006). Gamma-HOPdG is formed when acrolein, an alpha,beta-unsaturated aldehyde generated as an end product of lipid peroxidation or oxidation of polyamines, reacts with the N2 of guanine, leading to formation of a cyclic adduct. POLI incorporates dCMP opposite gamma-HOPdG as efficiently as opposite an undamaged G (Washington et al. 2004). EtAD is generated when DNA is exposed to chemical carcinogens, such as vinyl chloride, or epoxyaldehydes that are produced by lipid peroxidation. POLI shows preferential dTMP incorporation opposite to a template EtAD, but can also erroneously incorporate dCMP although with four times lower efficiency (Nair et al. 2006).
			R-HSA-5656158 (Reactome)	After it incorporates a dNMP opposite to a damaged template base, DNA polymerase iota (POLI) is unable to efficiently elongate the DNA strand further. The elongation step is performed by the DNA polymerase zeta complex (POLZ), composed of REV3L and MAD2L2 subunits (Johnson et al. 2000). POLK has also been implicated in the elongation step (Washington et al. 2004).
	RAD18:UBE2B,RBX1:CUL4:DDB1:DTL:PCNA:POLD,POLE:RPA:RFC:Damaged DNA Template	Arrow	R-HSA-5652005 (Reactome)
RAD18:UBE2B,RBX1:CUL4:DDB1:DTL:PCNA:POLD,POLE:RPA:RFC:Damaged DNA Template			R-HSA-5652009 (Reactome)
RAD18:UBE2B,RBX1:CUL4:DDB1:DTL:PCNA:POLD,POLE:RPA:RFC:Damaged DNA Template		mim-catalysis	R-HSA-5652009 (Reactome)
	RAD18:UBE2B,RBX1:CUL4:DDB1:DTL	Arrow	R-HSA-5652009 (Reactome)
RAD18:UBE2B,RBX1:CUL4:DDB1:DTL			R-HSA-5652005 (Reactome)
	RCHY1	Arrow	R-HSA-5655170 (Reactome)
RCHY1			R-HSA-5655142 (Reactome)
	REV1:MonoUb:K164-PCNA:RPA:RFC:(AP:Cyt)-DNA Template	Arrow	R-HSA-110308 (Reactome)
REV1:MonoUb:K164-PCNA:RPA:RFC:(AP:Cyt)-DNA Template			R-HSA-5652151 (Reactome)
	REV1:MonoUb:K164-PCNA:RPA:RFC:(AP:Cyt-mispairedPolydNMP)-DNA Template	Arrow	R-HSA-110311 (Reactome)
	REV1:MonoUb:K164-PCNA:RPA:RFC:AP-DNA Template	Arrow	R-HSA-110307 (Reactome)
REV1:MonoUb:K164-PCNA:RPA:RFC:AP-DNA Template			R-HSA-110308 (Reactome)
REV1:MonoUb:K164-PCNA:RPA:RFC:AP-DNA Template		mim-catalysis	R-HSA-110308 (Reactome)
	REV1	Arrow	R-HSA-5655965 (Reactome)
	REV1	Arrow	R-HSA-5656158 (Reactome)
REV1			R-HSA-110307 (Reactome)
REV1			R-HSA-5655835 (Reactome)
REV1			R-HSA-5656105 (Reactome)
REV3L			R-HSA-110322 (Reactome)
	SPRTN:POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template	Arrow	R-HSA-5654986 (Reactome)
SPRTN:POLH:MonoUb:K164-PCNA:RPA:RFC:(TT-CPD:AA-polydNMP)-DNA Template			R-HSA-5654985 (Reactome)
SPRTN			R-HSA-5654986 (Reactome)
	UBA7	Arrow	R-HSA-5653754 (Reactome)
	UBE2L6:TRIM25:DNA polymerase Y:MonoUb:K164-PCNA:RPA:RFC:TLS-DNA Template	Arrow	R-HSA-5653756 (Reactome)
UBE2L6:TRIM25:DNA polymerase Y:MonoUb:K164-PCNA:RPA:RFC:TLS-DNA Template			R-HSA-5653754 (Reactome)
UBE2L6:TRIM25:DNA polymerase Y:MonoUb:K164-PCNA:RPA:RFC:TLS-DNA Template		mim-catalysis	R-HSA-5653754 (Reactome)
	UBE2L6:TRIM25	Arrow	R-HSA-5653754 (Reactome)
UBE2L6:TRIM25			R-HSA-5653756 (Reactome)
	USP1(1-671)	Arrow	R-HSA-5655483 (Reactome)
	USP1(672-785)	Arrow	R-HSA-5655483 (Reactome)
	USP10:DNA polymerase Y:MonoUb:K164,ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template	Arrow	R-HSA-5653766 (Reactome)
USP10:DNA polymerase Y:MonoUb:K164,ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template			R-HSA-5653770 (Reactome)
USP10:DNA polymerase Y:MonoUb:K164,ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template		mim-catalysis	R-HSA-5653770 (Reactome)
	USP10	Arrow	R-HSA-5653770 (Reactome)
USP10			R-HSA-5653766 (Reactome)
	USP1:ZBTB32	Arrow	R-HSA-5655466 (Reactome)
USP1:ZBTB32			R-HSA-5655481 (Reactome)
USP1:ZBTB32			R-HSA-5655483 (Reactome)
USP1:ZBTB32		mim-catalysis	R-HSA-5655483 (Reactome)
	USP43:ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template	Arrow	R-HSA-5653780 (Reactome)
USP43:ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template			R-HSA-5653786 (Reactome)
USP43:ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template		mim-catalysis	R-HSA-5653786 (Reactome)
	USP43	Arrow	R-HSA-5653786 (Reactome)
USP43			R-HSA-5653780 (Reactome)
	ZBTB32	Arrow	R-HSA-5655483 (Reactome)
dATP			R-HSA-110317 (Reactome)
dCTP			R-HSA-110308 (Reactome)
dNTP			R-HSA-110311 (Reactome)
dNTP			R-HSA-110319 (Reactome)
dNTP			R-HSA-5653840 (Reactome)
dNTP			R-HSA-5655892 (Reactome)
dNTP			R-HSA-5655965 (Reactome)
dNTP			R-HSA-5656148 (Reactome)
dNTP			R-HSA-5656158 (Reactome)
	ubiquitin	Arrow	R-HSA-5653770 (Reactome)
	ubiquitin	Arrow	R-HSA-5655466 (Reactome)
ubiquitin			R-HSA-5652009 (Reactome)
ubiquitin			R-HSA-5655170 (Reactome)
ubiquitin			R-HSA-5655193 (Reactome)