日本名古屋大学Tomoo Ogi团队发现造成DNA损伤停滞的RNAPII的泛素化促进转录偶联修复。相关论文发表在2020年3月5日出版的《细胞》杂志上。
他们鉴定了一个RPB1-K1268的RNAPII中DNA损伤诱导的泛素化位点，该位点调节转录恢复和DNA损伤抗性。从机制上讲，RPB1-K1268泛素化通过转移机制刺激了核心-TFIIH复合物与失速的RNA聚合酶II（RNAPIIo）的缔合，该转移机制也涉及UVSSA-K414泛素化。他们开发了一种链特异性的ChIP-seq方法，该方法揭示了RPB1-K1268泛素化对于修复和解决DNA损伤处的转录瓶颈非常重要。最后，敲除RPB1-K1268R的小鼠表现出寿命短、早衰和神经退行性变。他们的研究结果表明，RNAPII泛素化为激活TC-NER以及同时处理DNA损伤的RNAPIIo提供了两级保护机制，共同防止长时间的转录停滞并阻止神经衰退。
研究人员表示，转录偶联核苷酸切除修复（TC-NER）通过延长DNA损伤处的长RNAPIIo来启动。响应DNA损伤中RNAPIIo的泛素化是一个进化保守的事件，但其在哺乳动物中的功能尚不清楚。
附：英文原文
Title: Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair
Author: 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 Masuda, Kinji Ohno, Shinichiro Nakada, Tomoji Mashimo, Koji Yamanaka, Martijn S. Luijsterburg, Tomoo Ogi
Issue&Volume: 2020-03-05
Abstract: Transcription-coupled nucleotide excision repair (TC-NER) is initiated by the stallingof elongating RNA polymerase II (RNAPIIo) at DNA lesions. The ubiquitination of RNAPIIoin response to DNA damage is an evolutionarily conserved event, but its function inmammals is unknown. Here, we identified a single DNA damage-induced ubiquitinationsite in RNAPII at RPB1-K1268, which regulates transcription recovery and DNA damageresistance. Mechanistically, RPB1-K1268 ubiquitination stimulates the associationof the core-TFIIH complex with stalled RNAPIIo through a transfer mechanism that alsoinvolves UVSSA-K414 ubiquitination. We developed a strand-specific ChIP-seq method,which revealed RPB1-K1268 ubiquitination is important for repair and the resolutionof transcriptional bottlenecks at DNA lesions. Finally, RPB1-K1268R knockin mice displayeda short life-span, premature aging, and neurodegeneration. Our results reveal RNAPIIubiquitination provides a two-tier protection mechanism by activating TC-NER and,in parallel, the processing of DNA damage-stalled RNAPIIo, which together preventprolonged transcription arrest and protect against neurodegeneration.
DOI: 10.1016/j.cell.2020.02.010
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30154-9