Circadian PERIOD proteins regulate TC-DSB repair through anchoring to the nuclear envelope

作者：Benjamin Le Bozec, Laure Guitton-Sert, Sarah Collins, Anne-Laure Finoux, Charlotte Payrault, Jessica Frison, Romane Carette, Vincent Rocher, Emmanuelle Guillou, Coline Arnould, Aude Guénolé, Marion Aguirrebengoa, Ikrame Lazar, Aline Marnef, Philippe Frit, Patrick Calsou, Thomas Mangeat, Nadine Puget, Gaëlle Legube · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2023 · DOI：10.1101/2023.05.11.540338 · 被引用次数：9 · 研究领域：DNA Repair Mechanisms、Nuclear Structure and Function、Genomics and Chromatin Dynamics

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 proteins from the PERIOD complex, a key module ensuring circadian oscillations, as novel TC-DSBR players. We show that the core PER complex protein PER2 is recruited at TC-DSBs and that it contributes to the targeting of TC-DSBs at the nuclear envelope (NE). At the NE, SUN1 and the Nuclear Pore Complex (NPC) act as docking sites for TC-DSBs and TC-DSB anchoring fosters RAD51 assembly. Impaired DSB localization at the NE results in elevated DSB clustering and translocation rate. In agreement, the circadian clock regulates TC-DSB anchoring to the NE, RAD51 assembly, and DSB clustering. Our study shows that DSB localization to the NPC is a conserved molecular pathway that also occurs in human cells and provides a direct link between the circadian rhythm and the response to DSBs occurring in active genes. This opens new therapeutic strategies for chemotherapies based on drugs that are inducing DSBs in active loci such as topoisomerase poisons.