Although TFIIH is mostly engaged in transcription as a general transcription factor under normal culture conditions, it rapidly switches to sites of DNA damage upon UV irradiation of cells. However, the precise mechanism underlying the recruitment of TFIIH to DNA lesions by XPC has remained unclear. In the present study, Okuda et al. have determined the structure of the acidic region of human XPC bound to the pleckstrin homology (PH) domain of TFIIH p62 using nuclear magnetic resonance (NMR) spectroscopy.
XPC uses a coupled folding and binding mode, and wraps around the basic surface of the p62 PH domain. The bound structure of XPC closely resembles the extended acidic string-like structures observed for the general transcription factor TFIIEα and the tumor suppressor p53 bound to the p62 PH domain; however, the structure reveals critical differences in the recognition site.
The key residues of XPC necessary for strong binding have been verified by mutational analyses using isothermal titration calorimetry (ITC) in vitro and immunoprecipitation in vivo. Alanine substitution of these key residues compromised the recruitment of TFIIH to sites of DNA damage, UV resistance, and the repair of UV-induced pyrimidine-pyrimidone (6-4) photoproducts in XPC-deficient cells stably transformed to express XPC protein. This study sheds light on the mechanism for functional cooperation between XPC and TFIIH in the early stage of global genomic Nucleotide excision repair.
Structural Insight into the Mechanism of TFIIH Recognition by the Acidic String of the Nucleotide Excision Repair Factor XPC. Okuda M, Kinoshita M, Kakumu E, Sugasawa K, Nishimura Y. Structure. 2015;23(10):1827-37.