Signaling Pathways, Chemical and Biological Modulators of Nucleotide Excision Repair: The Faithful Shield against UV Genotoxicity

Figure 2

Schematic representation of nucleotide excision repair. Recognition of DNA damage differs between transcription-coupled NER (TC-NER) and global genome NER (GG-NER). (1) Damage Recognition. In TC-NER, the stalled RNA polymerase in transcriptionally active genes favors the recruitment of Cockayne syndrome proteins A and B (CSA and CSB). In GG-NER, the damage is recognized by XPC and its partners RAD23B (Rad 23 homologue B) and CEN (centrin 2) if it is a helix-distorting lesion. A mild distorting lesion in this subpathway is recognized by XPE and DDB1 (DNA damage-binding protein 1). The following steps are the same for both GG-NER and TC-NER. (2) DNA unwinding. TFIIH is recruited and it contains XPB and XPD helicases that catalyze the opening of the DNA. (3) Damage verification. XPA, XPG, and RPA1 are recruited. XPA verifies the DNA damage while RPA1 binds to the single-stranded DNA. (4) Incision. XPF that is in a complex with ERCC1 is recruited. Both XPF and XPG are nucleases that catalyze the incision of 5 and 3 of the damage, respectively. (5) DNA synthesis and ligation. The missing DNA sequence is synthesized by polymerase delta with the assistance of PCNA, RCF, and RPA1. DNA ligase 3 interacting with XRCC1 ligates the produced fragment leading to the formation of intact DNA. It should be noted that XPF-ERCC1 mediates the incision at the 5 end and then the polymerase with PCNA, RCF, and PCNA will aid in displacing the damaged strand to be finally followed by the incision at the 3 end by XPG. XPA-XPG: xeroderma pigmentosum protein A-G; NER: nucleotide excision repair; TC-NER: transcription-coupled nucleotide excision repair; GG-NER: global genome nucleotide excision repair; CSA and CSB: Cockayne syndrome proteins A and B; DDB1: DNA damage-binding protein 1; RAD23B: RAD 23 homologue B; Cen: centrin 2; TFIIH: transcription factor II H; RPA1: replication protein A; ERCC1: excision repair cross-complementation group 1; PCNA: proliferating cell nuclear antigen; RCF: replication factor C; Polδ: polymerase delta; LIG3: DNA ligase 3; XRCC1: X-ray repair cross-complementing protein 1.