Fig. 7. Reciprocal coordination of DNA damage detection and handover in GG-NER.

DDB2 binds directly to UV-photoproducts, thereby stimulating XPC recruitment to CPDs and 6-4PPs. The CRL4 E3 ubiquitin ligase is activated upon DDB2 binding and ubiquitylates DDB2 and XPC. TFIIH is recruited via an interaction between its subunit XPB with XPC (interaction depicted with dotted lines). Upon TFIIH binding, its trimeric CDK7-activating kinase (CAK) sub-complex is released and allows XPA binding, which further stimulates TFIIH’s XPD helicase that unwinds the DNA in the 5′–3′ direction while scanning for helicase blocking lesions. This configuration facilitates further interaction between TFIIH and XPC by allowing GTF2H1 to interact with XPC. Recruitment of TFIIH and ensuing damage verification promote the stable association of XPC with the undamaged strand and simultaneously facilitate the displacement of DDB2, which is also promoted by ubiquitylation-mediated extraction by VCP (1). The subsequent degradation of DDB2 (2) regulates its availability to rebind to lesions, possibly to avoid competition with the emerging NER pre-incision complex. The formation of a stable ternary XPC-TFIIH-XPA damage verification complex on the lesion and the unpaired DNA surrounding the lesion (created by this complex) provide substrate for the structure-specific endonucleases XPF-ERRC1 and XPG (the latter coinciding with XPC dissociation), which completes the formation of the pre-incision complex.