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

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.

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Publication Details

Journal
Molecular Cell
Published
2025-11-20
DOI
https://doi.org/10.1016/j.molcel.2025.10.027
Citations
2
Primary Topic
Nuclear Structure and Function
Type
article
Field-Weighted Citation Impact
1.61
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article

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

Aline Marnef, Nadine Puget, Sara B Collins, Ikrame Lazar et al.
2 citations
Molecular Cell
Nuclear Structure and Function
1.61
article

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

Aline Marnef, Nadine Puget, Sara B Collins, Ikrame Lazar, Aude Guénolé, Anne-Laure Finoux, Marion Aguirrebengoa, Emmanuelle Guillou, Virginie Jouffret, Philippe Frit, Laure Guitton-Sert, Gaëlle Legube, Vincent Rocher, Patrick Calsou, Thomas Mangeat, Coline Arnould, Benjamin Le Bozec, Vanessa Dougados, Romane Carette, Jessica Frison, Charlotte Payrault
article en
2 citations

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, 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.

Molecular CellVol. 85(24)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Institut de Pharmacologie et de Biologie Structurale (FR)
Openalex Percentile: Top 14%
Nuclear Structure and Function
1.61
DOIOpen Access PDFOpenAlex
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