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

Cell. 2020 Mar 19;180(6):1228-1244.e24. doi: 10.1016/j.cell.2020.02.010.

Yuka Nakazawa ¹, Yuichiro Hara ¹, Yasuyoshi Oka ¹, Okiru Komine ², Diana van den Heuvel ³, Chaowan Guo ¹, Yasukazu Daigaku ⁴, Mayu Isono ¹, Yuxi He ¹, Mayuko Shimada ¹, Kana Kato ¹, Nan Jia ¹, Satoru Hashimoto ¹, Yuko Kotani ⁵, Yuka Miyoshi ², Miyako Tanaka ⁶, Akira Sobue ², Norisato Mitsutake ⁷, Takayoshi Suganami ⁶, Akio Masuda ⁸, Kinji Ohno ⁸, Shinichiro Nakada ⁹, Tomoji Mashimo ¹⁰, Koji Yamanaka ², Martijn S Luijsterburg ³, Tomoo Ogi ¹¹

Affiliations

1 Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan; Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
2 Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan; Department of Neuroscience and Pathobiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3 Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
4 Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan; Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
5 Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Osaka, Japan; Genome Editing Research and Development (R&D) Center, Graduate School of Medicine, Osaka University, Osaka, Japan.
6 Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan.
7 Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
8 Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
9 Department of Bioregulation and Cellular Response, Graduate School of Medicine, Osaka University, Osaka, Japan; Institute for Advanced Co-Creation Studies, Osaka University, Osaka, Japan.
10 Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Osaka, Japan; Genome Editing Research and Development (R&D) Center, Graduate School of Medicine, Osaka University, Osaka, Japan; Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
11 Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan; Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: [email protected].

PMID: 32142649 DOI: 10.1016/j.cell.2020.02.010

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.

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.

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