Benjamin Le Bozec, Laure Guitton-Sert, Sara B Collins, Anne-Laure Finoux, Charlotte Payrault, Emmanuelle Guillou, Marion Aguirrebengoa, Vanessa Dougados, Virginie Jouffret, Jessica Frison, Romane Carette, Vincent Rocher, Coline Arnould, Aude Guénolé, Ikrame Lazar, Aline Marnef, Philippe Frit, Patrick Calsou, Thomas Mangeat, Nadine Puget, Gaëlle Legube
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 proteins from the PERIOD complex, ensuring circadian oscillations, as previously unknown TC-DSBR players. We show that PER2 is recruited at TC-DSBs and contributes to their targeting to the nuclear envelope (NE), where SUN1 and the nuclear pore complex (NPC) act as docking sites. TC-DSB anchoring at the NE fosters RAD51 assembly and prevents DSB clustering and translocations. In agreement, the circadian clock regulates TC-DSB targeting to the NE, RAD51 assembly, and DSB clustering. Our study shows a direct link between the circadian rhythm and the response to DSBs in transcribed genes, opening strategies for chrono-chemotherapies based on topoisomerase poisons that induce DSBs in active loci.