Figure 2

Nucleotide excision repair (NER) repairs UV-induced pyrimidine dimers, intra-strand and protein-DNA crosslinks, and a wide range of bulky chemical adducts [11]. Its two subpathways global genomic repair (GG-NER) and transcription-coupled repair (TC-NER) differ in their damage recognition. DNA distortions anywhere in the genome are recognized by XPC. Lesions that cause only minor distortions, such as UV-induced cyclobutane pyrimidine dimers (CPD) are recognized by the damage DNA binding complex (DDB) composed of DDB1 and DDB2 (encoded by the XPE gene). DDB induces a strong kink in the DNA, enhancing its recognition by XPC. The XPC and DDB complexes are dispensable for the TC-NER subpathway that relies on RNA Pol II for the recognition of DNA damage. When RNA Pol II encounters a lesion that blocks its progression, it recruits CSA, CSB and XAB2. Either XPC in GG-NER or CSB and CSA in TC-NER then recruit further NER factors, including the transcription factor TFIIH to the damage site. The XPD and XPB subunits of TFIIH (depicted separately to point out their essential role in NER) unwind the DNA around the lesion. This process requires the helicase activity of XPD and the ATPase (but not the helicase) activity of XPB. XPG stabilizes the interaction between TFIIH and XPD. The opened denaturation bubble is stabilized by the XPA complex (XPA and the heterotrimer RNA), which also participates in the proofreading step (verification of the presence of a lesion and identification of the damaged strand). The damaged strand is incised on the 3' side of the lesion by XPG and on the 5' by the ERCC1-XPF heterodimer. The gap left by the excised oligonucleotide is filled by one of the replicative DNA polymerases (Pol δ or Pol ε) using the undamaged strand as a template and sealed by either ligase I or III.