期刊
CELL
卷 180, 期 6, 页码 1228-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2020.02.010
关键词
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资金
- Special Coordination Funds for Rare and Intractable Diseases from Japan Agency for Medical Research and Development (AMED) [JP19ek0109281, JP19ek0109229, JP19ek0109301]
- Japan Society for the Promotion of Science [JP15H02654, JP17H00783]
- Uehara Memorial Foundation
- Daiko Foundation
- Takeda Science Foundation
- KAKENHI [JP17H01877]
- Tokyo Biochemical Research Foundation (TBRF)
- LUMC research fellowship
- NWO-VIDI [016.161.320]
Transcription-coupled nucleotide excision repair (TC-NER) is initiated by the stalling of elongating RNA polymerase H (RNAPIIo) at DNA lesions. The ubiquitination of RNAPIIo in response to DNA damage is an evolutionarily conserved event, but its function in mammals is unknown. Here, we identified a single DNA damage-induced ubiquitination site in RNAPII at RPB1-K1268, which regulates transcription recovery and DNA damage resistance. Mechanistically, RPB1-K1268 ubiquitination stimulates the association of the core-TFIIH complex with stalled RNAPIIo through a transfer mechanism that also involves UVSSA-K414 ubiquitination. We developed a strand-specific ChIP-seq method, which revealed RPB1-K1268 ubiquitination is important for repair and the resolution of transcriptional bottlenecks at DNA lesions. Finally, RPB1-K1268R knockin mice displayed a short life-span, premature aging, and neurodegeneration. Our results reveal RNAPII ubiquitination provides a two-tier protection mechanism by activating TC-NER and, in parallel, the processing of DNA damage-stalled RNAPIIo, which together prevent prolonged transcription arrest and protect against neurodegeneration.
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