XERODERMA-PIGMENTOSUM GROUP-C PROTEIN COMPLEX IS THE INITIATOR OF GLOBAL GENOME NUCLEOTIDE EXCISION-REPAIR

The XPC-HR23B complex is specifically involved in global genome but no t transcription-coupled nucleotide excision repair (NER). Its function is unknown. Using a novel DNA damage recognition-competition assay, w e identified XPC-HR23B as the earliest damage detector to initiate NER : it acts before the known damage-binding protein XPA. Coimmunoprecipi tation and DNase I footprinting show that XPC-HR23B binds to a variety of NER lesions. These results resolve the function of XPC-HR23B, defi ne the first NER stages, and suggest a two-step mechanism of damage re cognition involving damage detection by XPC-HR23B followed by damage v erification by XPA. This provides a plausible explanation for the extr eme damage specificity exhibited by global genome repair. In analogy, in the transcription-coupled NER subpathway, RNA polymerase II may tak e the role of XPC. After this subpathway-specific initial lesion detec tion, XPA may function as a common damage verifier and adaptor to the core of the NER apparatus.