| RRC ID |
6775
|
| 著者 |
Yasuda G, Nishi R, Watanabe E, Mori T, Iwai S, Orioli D, Stefanini M, Hanaoka F, Sugasawa K.
|
| タイトル |
In vivo destabilization and functional defects of the xeroderma pigmentosum C protein caused by a pathogenic missense mutation.
|
| ジャーナル |
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.
|
| 巻・号 |
27(19)
|
| ページ |
6606-14
|
| 公開日 |
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
|
| 引用数 |
33
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
NB1RGB(RCB0222) |
