RRC ID 58799
著者 Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Kato K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg MS, Ogi T.
タイトル Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair.
ジャーナル Cell
Abstract Transcription-coupled nucleotide excision repair (TC-NER) is initiated by the stalling of elongating RNA polymerase II (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.
巻・号 180(6)
ページ 1228-1244.e24
公開日 2020-3-19
DOI 10.1016/j.cell.2020.02.010
PII S0092-8674(20)30154-9
PMID 32142649
MeSH Animals Carrier Proteins / genetics Carrier Proteins / metabolism DNA / metabolism DNA Damage / physiology DNA Helicases / metabolism DNA Repair / physiology* DNA Repair Enzymes / genetics DNA Repair Enzymes / metabolism Female HCT116 Cells HEK293 Cells HeLa Cells Humans Male Mice Mice, Inbred C57BL Mice, Knockout RNA Polymerase II / genetics RNA Polymerase II / metabolism* Ubiquitination
IF 38.637
引用数 3
リソース情報
ヒト・動物細胞 HCT116(RCB2979)