A single RNA polymerase II ubiquitylation site coordinates transcription with the DNA damage response

In response to transcription-blocking DNA damage, cells orchestrate a multi-pronged
reaction, involving transcription-coupled DNA repair, degradation of RNAPII and
genome-wide transcription shutdown. How these responses are connected has
remained unclear. Here we show that damage-induced 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. It is also crucial for transcriptional shutdown,
in the absence of which cells display dramatic transcriptome alterations. Additionally,
regulation of RNAPII stability is central to transcription recovery – indeed, depletion of
the RNAPII pool 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 programmes, in genome instability disorders and
even normal cells.