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.