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

Yuka Nakazawa, Yuichiro Hara, Yasuyoshi Oka, Okiru Komine, Diana van den Heuvel, Chaowan Guo, Yasukazu Daigaku, Mayu Isono, Yuxi He, Mayuko Shimada, Kana Kato, Nan Jia, Satoru Hashimoto, Yuko Kotani, Yuka Miyoshi, Miyako Tanaka, Akira Sobue, Norisato Mitsutake, Takayoshi Suganami, Akio MasudaKinji Ohno, Shinichiro Nakada, Tomoji Mashimo, Koji Yamanaka, Martijn S. Luijsterburg, Tomoo Ogi

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1228-1244.e24
JournalCell
Volume180
Issue number6
DOIs
Publication statusPublished - 2020 Mar 19

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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