Circadian PERIOD proteins regulate 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 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.