372
Pathway
Nucleotide Excision Repair
In order to pass genetic information from one generation to the next, all organisms must accurately replicate their genomes during each cell division. This includes the nuclear genome and mitochondrial and chloroplast genomes. These are normally replicated with high fidelity that is achieved through the action of accurate DNA repair. Nucleotide Excision Repair is one os several mechanisms of DNA repair. Nucleotide excision repair (NER) operates on base damage caused by exogenous agents (such as mutagenic and carcinogenic chemicals and photoproducts generated by sunlight exposure) that cause alterations in the chemistry and structure of the DNA duplex . Such damage is recognized by a protein called XPC, which is stably bound to another protein called HHRAD23B (R23). The binding of the XPC–HHRAD23 heterodimeric subcomplex is followed by the binding of several other proteins (XPA, RPA, TFIIH and XPG). Of these, XPA and RPA are believed to facilitate specific recognition of base damage. TFIIH is a subcomplex of the RNA polymerase II transcription initiation machinery which also operates during NER. It consists of six subunits and contains two DNA helicase activities (XPB and XPD) that unwind the DNA duplex in the immediate vicinity of the base damage. This local denaturation generates a bubble in the DNA, the ends of which comprise junctions between duplex and single-stranded DNA. The subsequent binding of the ERCC1–XPF heterodimeric subcomplex generates a completely assembled NER multiprotein complex. XPG is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 3’ to the site of base damage. Conversely, the ERCC1–XPF heterodimeric protein is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 5’ to the site of base damage. This bimodal incision generates an oligonucleotide fragment 27–30 nucleotides in length which includes the damaged base. This fragment is excised from the genome, concomitant with restoring the potential 27–30 nucleotide gap by repair synthesis. Repair synthesis requires DNA polymerases or , as well as the accessory replication proteins PCNA, RPA and RFC. The covalent integrity of the damaged strand is then restored by DNA ligase. Collectively, these biochemical events return the damaged DNA to its native chemistry and configuration. ERCC1, excision repair cross-complementing 1; PCNA, proliferating cell nuclear antigen; POL, polymerase; RFC, replication factor C; RPA, replication protein A; TFIIH, transcription factor IIH; XP, xeroderma pigmentosum.
Metabolic
PW000457
Center
PathwayVisualizationContext493
3000
2000
#000099
PathwayVisualization142
372
Nucleotide Excision Repair
In order to pass genetic information from one generation to the next, all organisms must accurately replicate their genomes during each cell division. This includes the nuclear genome and mitochondrial and chloroplast genomes. These are normally replicated with high fidelity that is achieved through the action of accurate DNA repair. Nucleotide Excision Repair is one os several mechanisms of DNA repair. Nucleotide excision repair (NER) operates on base damage caused by exogenous agents (such as mutagenic and carcinogenic chemicals and photoproducts generated by sunlight exposure) that cause alterations in the chemistry and structure of the DNA duplex . Such damage is recognized by a protein called XPC, which is stably bound to another protein called HHRAD23B (R23). The binding of the XPC–HHRAD23 heterodimeric subcomplex is followed by the binding of several other proteins (XPA, RPA, TFIIH and XPG). Of these, XPA and RPA are believed to facilitate specific recognition of base damage. TFIIH is a subcomplex of the RNA polymerase II transcription initiation machinery which also operates during NER. It consists of six subunits and contains two DNA helicase activities (XPB and XPD) that unwind the DNA duplex in the immediate vicinity of the base damage. This local denaturation generates a bubble in the DNA, the ends of which comprise junctions between duplex and single-stranded DNA. The subsequent binding of the ERCC1–XPF heterodimeric subcomplex generates a completely assembled NER multiprotein complex. XPG is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 3’ to the site of base damage. Conversely, the ERCC1–XPF heterodimeric protein is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 5’ to the site of base damage. This bimodal incision generates an oligonucleotide fragment 27–30 nucleotides in length which includes the damaged base. This fragment is excised from the genome, concomitant with restoring the potential 27–30 nucleotide gap by repair synthesis. Repair synthesis requires DNA polymerases or , as well as the accessory replication proteins PCNA, RPA and RFC. The covalent integrity of the damaged strand is then restored by DNA ligase. Collectively, these biochemical events return the damaged DNA to its native chemistry and configuration. ERCC1, excision repair cross-complementing 1; PCNA, proliferating cell nuclear antigen; POL, polymerase; RFC, replication factor C; RPA, replication protein A; TFIIH, transcription factor IIH; XP, xeroderma pigmentosum.
Metabolic
1
1539
18166979
McCulloch SD, Kunkel TA: The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res. 2008 Jan;18(1):148-61. doi: 10.1038/cr.2008.4.
372
Pathway
1540
11900249
Friedberg EC: How nucleotide excision repair protects against cancer. Nat Rev Cancer. 2001 Oct;1(1):22-33. doi: 10.1038/35094000.
372
Pathway
1
Cell
CL:0000000
1
Homo sapiens
9606
Eukaryote
Human
15
Nucleus
GO:0005634
5
Cytoplasm
GO:0005737
23
15
1
1
PW_BS000023
8
5
1
1
PW_BS000008
27
15
1
PW_BS000027
5808
UV excision repair protein RAD23 homolog A
P54725
1
8511
23
5809
DNA repair protein complementing XP-A cells
P23025
1
8512
23
3933
TFIIH basal transcription factor complex helicase XPD subunit
P18074
ATP-dependent 5'-3' DNA helicase, component of the core-TFIIH basal transcription factor. Involved in nucleotide excision repair (NER) of DNA by opening DNA around the damage, and in RNA transcription by RNA polymerase II by anchoring the CDK-activating kinase (CAK) complex, composed of CDK7, cyclin H and MAT1, to the core-TFIIH complex. Involved in the regulation of vitamin-D receptor activity. As part of the mitotic spindle-associated MMXD complex it plays a role in chromosome segregation. Might have a role in aging process and could play a causative role in the generation of skin cancers.
HMDBP08717
ERCC2
19q13.3
BC108255
1
3.6.4.12
5810
Replication factor C subunit 1
P35251
1
8513
23
5811
Proliferating cell nuclear antigen
P12004
1
8514
23
80376
8
80844
27
4520
DNA-directed RNA polymerase I subunit RPA1
O95602
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic core component of RNA polymerase I which synthesizes ribosomal RNA precursors. Forms the polymerase active center together with the second largest subunit. A single stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol I. A bridging helix emanates from RPA1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol I by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition (By similarity).
HMDBP09345
POLR1A
2p11.2
AH007280
1
2.7.7.6
5812
DNA repair protein complementing XP-G cells
P28715
1
3.1.-.-
8515
23
4050
DNA repair endonuclease XPF
Q92889
Structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair. Involved in homologous recombination that assists in removing interstrand cross-link
HMDBP08835
ERCC4
16p13.12
U64315
1
3.1.-.-
8516
23
5518
DNA polymerase sigma
Q5XG87
DNA polymerase, probably involved in DNA repair. May play a role in sister chromatid cohesion. Does not play a role in replication-dependent histone mRNA degradation.
HMDBP11873
PAPD7
5p15
BC084567
1
2.7.7.19
901
DNA polymerase epsilon catalytic subunit A
Q07864
Participates in DNA repair and in chromosomal DNA replication.
HMDBP00961
POLE
12q24.3
AY273166
1
2.7.7.7
8517
23
625
DNA ligase 1
P18858
DNA ligase that seals nicks in double-stranded DNA during DNA replication, DNA recombination and DNA repair.
HMDBP00660
LIG1
19q13.2-q13.3
AK314210
1
6.5.1.1
8518
23
6109
5808
23
188
false
890
400
8
subunit
regular
300
140
6110
5809
23
186
false
840
750
8
subunit
regular
150
70
6111
5808
23
188
false
955
770
8
subunit
regular
300
140
6112
5808
23
188
false
1045
1195
8
subunit
regular
300
140
6113
5808
23
188
false
1045
1625
8
subunit
regular
300
140
6114
3933
188
false
650
845
8
subunit
regular
300
140
6115
3933
188
false
770
1260
8
subunit
regular
300
140
6116
3933
188
false
700
1715
8
subunit
regular
300
140
6117
5810
23
186
false
415
2360
8
subunit
regular
150
70
6118
5811
23
186
false
525
2205
8
subunit
regular
150
70
6119
4520
188
false
935
905
8
subunit
regular
300
140
6120
4520
188
false
1005
1330
8
subunit
regular
300
140
6121
4520
188
false
1000
1755
8
subunit
regular
300
140
6122
4520
188
false
1015
2205
8
subunit
regular
300
140
6123
5812
23
188
false
1175
850
8
subunit
regular
300
140
6124
5812
23
188
false
1250
1265
8
subunit
regular
300
140
6125
5812
23
188
false
1250
1685
8
subunit
regular
300
140
6126
5809
23
186
false
930
1160
8
subunit
regular
150
70
6127
5809
23
186
false
920
1590
8
subunit
regular
150
70
6129
4050
23
186
false
625
1280
8
subunit
regular
150
70
6130
4050
23
186
false
525
1690
8
subunit
regular
150
70
6131
5518
188
false
690
2155
8
subunit
regular
300
140
6132
901
23
188
false
690
2235
8
subunit
regular
300
140
6133
625
23
188
false
1275
2175
8
subunit
regular
300
140
72
6109
73
6110
74
6111
75
6112
76
6113
77
6114
78
6115
79
6116
80
6117
81
6118
82
6119
83
6120
84
6121
85
6122
86
6123
87
6124
88
6125
89
6126
90
6127
92
6129
93
6130
94
6131
95
6132
96
6133
906
190
10
20
1.0
1.0
0
2
40
1900
2700