Regulation of the RNAPII Pool Is Integral to the DNA Damage Response

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. [Display omitted] •Specific RPB1 K1268 ubiquitylation targets RNAPII for UV-induced proteolysis•RPB1 K1268 ubiquitylation is required for surviving DNA damage•Control of the RNAPII pool via degradation regulates the transcriptome after UV•Lack of transcription recovery in Cockayne syndrome is caused by unstable RNAPII Control of the pool of available RNA polymerase II shapes how cells respond to UV stress and the efficacy of the resulting damage response.