英国弗朗西斯·克里克研究所Jesper Q. Svejstrup团队近日取得一项新成果。他们的研究发现RNA聚合酶II（RNAPII）库的调节是DNA损伤反应不可或缺的部分。相关论文于2020年3月5日发表在《细胞》杂志上。
他们发现单个赖氨酸（RPB1 K1268）上的RNAPII自身的泛素化是DNA损伤应答协调的焦点，并提供了对这些应答如何关联的见解。K1268泛素化会影响DNA修复并发出RNAPII降解信号，这对于幸存的遗传毒性损伤至关重要。RNAPII降解会导致转录起始的关闭，在这种情况下，没有这些细胞会显示出明显的转录组改变。此外，RNAPII稳定性的调节是转录恢复的关键-持续的RNAPII消耗奠定了Cockayne综合征B细胞中该过程失败的基础。这些数据揭示了细胞RNAPII库的调节是DNA损伤反应不可或缺的部分，并开启了一扇有趣的大门，即RNAPII库的大小通常会影响基因组不稳定，甚至影响正常细胞中的细胞特异性转录程序。
据了解，为了响应阻止转录的DNA损伤，细胞编排了多管齐下的反应，涉及转录偶联的DNA修复、RNAPII的降解和全基因组转录关闭。
附：英文原文
Title: Regulation of the RNAPII Pool Is Integral to the DNA Damage Response
Author: Ana Tufegdi Vidakovi, Richard Mitter, Gavin P. Kelly, Michelle Neumann, Michelle Harreman, Marta Rodríguez-Martínez, Anna Herlihy, Juston C. Weems, Stefan Boeing, Vesela Encheva, Liam Gaul, Laura Milligan, David Tollervey, Ronald C. Conaway, Joan W. Conaway, Ambrosius P. Snijders, Aengus Stewart, Jesper Q. Svejstrup
Issue&Volume: 2020-03-05
Abstract: In response to transcription-blocking DNA damage, cells orchestrate a multi-pronged reaction, involving transcription-coupled DNA repair, degradation of RNA polymerase II (RNAPII), and genome-wide transcription shutdown. Here, we provide insight into how these responses are connected by the finding that ubiquitylation of RNAPII itself, at a single lysine (RPB1 K1268), is the focal point for DNA-damage-response coordination. K1268 ubiquitylation affects DNA repair and signals RNAPII degradation, essential for surviving genotoxic insult. RNAPII degradation results in a shutdown of transcriptional initiation, in the absence of which cells display dramatic transcriptome alterations. Additionally, regulation of RNAPII stability is central to transcription recovery—persistent RNAPII depletion underlies the failure of this process in Cockayne syndrome B cells. These data expose regulation of global RNAPII levels as integral to the cellular DNA-damage response and open the intriguing possibility that RNAPII pool size generally affects cell-specific transcription programs in genome instability disorders and even normal cells.
DOI: 10.1016/j.cell.2020.02.009
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30153-7