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 not transcription-coupled nucleotide excision repair (NER). Its function is unknown. Using a novel DNA damage recognition-competition assay, we identified XPC-HR23B as the earliest damage detector to initiate NER: it acts before the known damage-binding protein XPA. Coimmunoprecipitation and DNase I footprinting show that XPC-HR23B binds to a variety of NER lesions. These results resolve the function of XPC-HR23B, define the first NER stages, and suggest a two-step mechanism of damage recognition involving damage detection by XPC-HR23B followed by damage verification by XPA. This provides a plausible explanation for the extreme damage specificity exhibited by global genome repair. In analogy, in the transcription-coupled NER subpathway, RNA polymerase II may take the role of XPC. After this subpathway-specific initial lesion detection, XPA may function as a common damage verifier and adaptor to the core of the NER apparatus.
Sugasawa
K
K
Department of Cell Biology and Genetics, Medical Genetic Centre, Erasmus University, Rotterdam, The Netherlands. sugasawa@postman.riken.go.jp
Ng
J M
JM
Masutani
C
C
Iwai
S
S
van der Spek
P J
PJ
Eker
A P
AP
Hanaoka
F
F
Bootsma
D
D
Hoeijmakers
J H
JH
D001483:Base Sequence; D001667:Binding, Competitive; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015894:Genome, Human; D006801:Humans; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008954:Models, Biological; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C086984:XPC protein, human; D004247:DNA