Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress

The transcriptional response to genotoxic stress involves gene expression arrest, followed by recovery of mRNA synthesis (RRS) after DNA repair. Using a small-scale RNA interference screen, we found that the lack of the EXD2 nuclease impaired RRS and decreased cell survival after UV irradiation, without affecting DNA repair. Overexpression of wild-type, but not nuclease-dead EXD2, restored RRS and cell survival. We observed that UV irradiation triggered recruitment of EXD2 to chromatin where the nuclease transiently interacts with RNA Polymerase II (RNAPII) to promote the degradation of nascent mRNAs synthesized at the time of genotoxic attack. Reconstitution of the EXD2-RNAPII partnership on a transcribed DNA template in vitro showed that EXD2 primarily interacts with an elongation-blocked RNAPII and efficiently digest mRNA. Overall, our data highlight a crucial new step in the transcriptional response to genotoxic attack in which EXD2 interacts with elongation-stalled RNAPII on chromatin to degrade the associated nascent mRNA, allowing transcription restart after DNA repair.