RRC ID 6775
Author Yasuda G, Nishi R, Watanabe E, Mori T, Iwai S, Orioli D, Stefanini M, Hanaoka F, Sugasawa K.
Title In vivo destabilization and functional defects of the xeroderma pigmentosum C protein caused by a pathogenic missense mutation.
Journal Mol Cell Biol
Abstract Xeroderma pigmentosum group C (XPC) protein plays an essential role in DNA damage recognition in mammalian global genome nucleotide excision repair (NER). Here, we analyze the functional basis of NER inactivation caused by a single amino acid substitution (Trp to Ser at position 690) in XPC, previously identified in the XPC patient XP13PV. The Trp690Ser change dramatically affects the in vivo stability of the XPC protein, thereby causing a significant reduction of its steady-state level in XP13PV fibroblasts. Despite normal heterotrimeric complex formation and physical interactions with other NER factors, the mutant XPC protein lacks binding affinity for both undamaged and damaged DNA. Thus, this single amino acid substitution is sufficient to compromise XPC function through both quantitative and qualitative alterations of the protein. Although the mutant XPC fails to recognize damaged DNA, it is still capable of accumulating in a UV-damaged DNA-binding protein (UV-DDB)-dependent manner to UV-damaged subnuclear domains. However, the NER factors transcription factor IIH and XPA failed to colocalize stably with the mutant XPC. As well as highlighting the importance of UV-DDB in recruiting XPC to UV-damaged sites, these findings demonstrate the role of DNA binding by XPC in the assembly of subsequent NER intermediate complexes.
Volume 27(19)
Pages 6606-14
Published 2007-10-1
DOI 10.1128/MCB.02166-06
PII MCB.02166-06
PMID 17682058
PMC PMC2099227
MeSH Amino Acid Sequence Animals Cells, Cultured DNA / genetics DNA / metabolism DNA / radiation effects DNA Damage DNA Repair* DNA-Binding Proteins* / genetics DNA-Binding Proteins* / metabolism Fibroblasts / cytology Fibroblasts / physiology Humans Molecular Sequence Data Mutation, Missense* Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / metabolism Sequence Alignment Sequence Homology, Amino Acid Ultraviolet Rays Xeroderma Pigmentosum* / genetics Xeroderma Pigmentosum* / metabolism
IF 3.611
Times Cited 33
Human and Animal Cells NB1RGB(RCB0222)