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.

为了应对转录阻断性 DNA 损伤，细胞会协调多管齐下的反应，包括转录偶联 DNA 修复、RNA 聚合酶 II (RNAPII) 降解和全基因组转录关闭。在这里，我们发现 RNAPII 本身在单个赖氨酸 (RPB1 K ₁₂₆₈ ) 上的泛素化是 DNA 损伤反应协调的焦点，从而深入了解这些反应是如何联系起来的。 K ₁₂₆₈泛素化影响 DNA 修复并发出 RNAPII 降解信号，这对于抵抗基因毒性损伤至关重要。 RNAPII 降解会导致转录起始的关闭，在没有转录起始的情况下，细胞会表现出戏剧性的转录组改变。此外，RNAPII 稳定性的调节对于转录恢复至关重要——持续的 RNAPII 耗竭是科凯恩综合征 B 细胞中这一过程失败的基础。这些数据揭示了全局 RNAPII 水平的调节是细胞 DNA 损伤反应不可或缺的一部分，并揭示了一个有趣的可能性，即 RNAPII 池大小通常会影响基因组不稳定疾病甚至正常细胞中的细胞特异性转录程序。