Circadian PERIOD complex regulates TC-DSB repair through anchoring to the nuclear envelope

Abstract Repair of DNA Double-Strand Breaks (DSBs) produced in transcriptionally active chromatin occurs through a poorly characterized pathway called Transcription-Coupled DSB repair (TC-DSBR). Here, using a screening approach scoring multiple outputs in human cells, we identified the PER complex, a key module ensuring circadian oscillations, as a novel TC-DSBR player. Circadian rhythm has been involved in repair of UV-induced DNA damage but very little is known about its contribution to DSB repair pathways. We show that the PER complex is recruited at DSBs occurring in transcribed loci and we further found that the core protein PER2 contributes to targeting TC-DSBs at the nuclear envelope (NE) and to foster RAD51-mediated repair. PER2 deficiency triggers decreased DSB anchoring to the NE, resulting in an increase of DSB clustering and translocation frequency. In agreement, we found that the circadian clock also regulates DSB anchoring to the NE and RAD51 assembly. In conclusion, our study provides a direct link between the circadian rhythm and the response to DSBs occurring in active genes, opening new therapeutic strategies for chemotherapies based on topoisomerase poisons that mostly induce DSBs in active loci.