Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair

• Nakazawa, Yuka

• Hara, Yuichiro

• Oka, Yasuyoshi

• Komine, Okiru

• van den Heuvel, Diana

• Guo, Chaowan

• Daigaku, Yasukazu

• Isono, Mayu

• He, Yuxi

• Shimada, Mayuko

• Kato, Kana

• Jia, Nan

• Hashimoto, Satoru

• Kotani, Yuko

• Miyoshi, Yuka

• Tanaka, Miyako

• Sobue, Akira

• Mitsutake, Norisato

• Suganami, Takayoshi

• Masuda, Akio

• Ohno, Kinji

• Nakada, Shinichiro

• Mashimo, Tomoji

• Yamanaka, Koji

• Luijsterburg, Martijn S.

• Ogi, Tomoo

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.

Journal

• Cell

  Cell 180 (6), 1228-1244.e24, 2020-03-19

  Elsevier

Keywords

• RNA polymerase II
• RNAPII
• ubiquitination of RNAPII
• transcription coupled repair
• TCR
• nucleotide excision repair
• NER
• Cockayne syndrome
• CS
• UV-sensitive syndrome
• UVsS
• ChIP-seq
• UVSSA
• CRL/CSA/CSB
• TFIIH

Details

• CRID: 1050566774821632640
• NII Article ID: 120006871293
• DOI: 10.1016/j.cell.2020.02.010
• HANDLE: 2237/00032522
• ISSN: 00928674
• Web Site: https://nagoya.repo.nii.ac.jp/records/30336
• Web Site: https://api.elsevier.com/content/article/PII:S0092867420301549?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S0092867420301549?httpAccept=text/plain
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN