Transcription-coupled nucleotide excision repair in mammalian cells： molecular mechanisms and biological effects.pdfVIP

Gell Resea时) (2008) 18:73-84. @ 。 2008 IBGB , SIBS, GAS AII 时ghts reserved 1001-0602/08 $ 30.00 REVIEW www.nature.∞I rnJcr Transcription-coupled nucleotide excision repair in mamma- lian cells: molecular mechanisms and biological effects l l Maria Fousteri , Leon HF Mullenders Depar阳ent ofToxicogenetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leíden, The Netherlands The encounter of elongating RNA polymerase 11 (RNAPIIo) with DNA lesions has severe consequences for the ceU as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract prolonged blockage of transcription , the cell removes the RNAP lIo-blocking DNA lesions by transcription-coupled repair (TC-NER), a specialized subpathway ofnucleotide excision repair (NER). Exposure ofmice to UVB light or chemicals has elucidated that TC-NER is a critical SUI甘val pathway protecting against acute toxic and long-term effects (cancer) of genotoxic exposure. Deficiency in TC-NER is associated with mutations in the CSA and CSB genes giving rise to the rare hu- man dis。可der Cockayne syndrome (CS). Recent data suggest that CSA and CSB play differential roles in mammalian TC-NER: CSB as a repair coupling factor to attract NER proteins ,chromatin remodeUers and the CSA- E3-ubiquitin ligase complex to the staUed RNAP lIo. CSA is dispensable for attraction of NER proteins ,yet in cooperation with CSB is required to recruit XAB2 ,the nucleosomal binding protein HMGNl and TFIIS. The emerging picture ofTC-NER is complex: repair of transcription-blocking lesions occurs without displacement of the DNA damage-staUed RNAPIIo, and requires