Chromatin modifications and their consequences in response to lesions that are repaired by NER. Induction of NER-lesions (by e.g. UV-light), results in three chromatin-associated responses: checkpoint signalling, transcription inhibition and DNA repair, of which the latter includes the postulated “access, repair, restore” model [133]. Checkpoint signalling involves phosphorylation of H2AX by ATR, ubiquitination of H2A (H2A-Ub) and methylated lysine residues H3K79 and H4K20. H2A-Ub and H3K79me/H4K20me are likely involved in checkpoint signalling upon NER activation, analogous to the DSB-response where H2A ubiquitination by RNF8 is required for the binding of checkpoint protein 53BP1 to H3K79me/H4K20me. Dephosphorylation of residues S10 and T11 of H3, possibly involving HMGN1, might contribute to transcription inhibition upon NER-activation and allow acetylation of H3K9, suggested to induce an open chromatin conformation enhancing access of the repair machinery to DNA. Other chromatin remodelling events promoting access to DNA repair proteins are ubiquitination of H3 and H4 by DDB2, acetylation of H3K14 and H4 by GCN5 and possibly p300, nucleosome sliding by ACF and nucleosome removal by SWI/SNF. After the lesion has been repaired, reincorporation of histones by CAF1 and possibly FACT or NAP1L1 restores the chromatin to its pre-damage conformation. Question marks indicate speculative activities.

Mammalian nucleotide excision repair mechanism. Schematic representation of the mammalian GG-NER process subdivided into different steps. The TC-NER pathway only differs in the mode of detection, which occurs by lesion-stalled RNA polymerase II, and is omitted for simplicity. 1. DNA helix locally disturbed by a (e.g. UV-induced) NER-inducing lesion (indicated by a red star). 2. Binding of the two GG-NER-specific damage recognition complexes UV-DDB and XPC/HR23B/Cen2. 3. Lesion-bound XPC is a substrate for TFIIH and XPG. 4. The helicase activity of TFIIH (requiring ATP-hydrolysis) increases the local unwinding. This structure is stabilised by binding of XPA (damaged strand) and RPA (covers the opposite non-damaged strand). Likely, at his stage XPC is released. 5. The structure-specific nuclease XPF/ERCC1 binds the pre-incision complex. 6. XPG and XPF-ERCC1 incise 3’ and 5’ of the lesion, respectively, thereby releasing a stretch of 25-30 nucleotides including the lesion, after which most pre-incision factors release. RPA and XPG are thought to help loading of the (7.) replication factors, PCNA and either DNA polymerase δ or ε, that fill in the ss-gap. 8. The reaction is completed by the sealing activity of either ligase 1 or the complex XRCC1/Ligase 3.