Regulation of the RNAPII pool is integral to the DNA damage responseMore about Open Access at the Crick
Authors listAna Tufegdžić Vidaković 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 Bram Snijders Aengus Stewart Jesper Svejstrup
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.
Issue number 6