- Research Highlight
- Published: 22 December 2025
Circadian biology
Nature Chemical Biology (2025)Cite this article
DNA double-strand breaks (DSBs) on active genes can interfere with gene transcription. High-throughput genome-wide sequencing studies have previously shown that DSBs are prevalent in the loci of active genes, although the mechanisms by how transcription can induce DSBs are still not fully resolved. Furthermore, these DSBs are rapidly repaired, which has suggested a transcription-coupled DSB repair (TC-DSBR) pathway distinct from the pathway for global genome DSB scanning and repair of inactive loci. Now, Le Bozec et al. have discovered unique molecular players involved…
- Research Highlight
- Published: 22 December 2025
Circadian biology
Nature Chemical Biology (2025)Cite this article
DNA double-strand breaks (DSBs) on active genes can interfere with gene transcription. High-throughput genome-wide sequencing studies have previously shown that DSBs are prevalent in the loci of active genes, although the mechanisms by how transcription can induce DSBs are still not fully resolved. Furthermore, these DSBs are rapidly repaired, which has suggested a transcription-coupled DSB repair (TC-DSBR) pathway distinct from the pathway for global genome DSB scanning and repair of inactive loci. Now, Le Bozec et al. have discovered unique molecular players involved in TC-DSBR.
An initial siRNA library screen complemented by a candidate approach identified that the knockdown of various components of the circadian clock PERIOD (PER) complex, such as PER1, PER2, NONO, DDX5, DDX17 and SETX, altered TC-DSBR. ChIP–seq showed that PER2 specifically bound to TC-DSBs. Further analysis showed that SUN1, an inner nuclear membrane protein of the linker of nucleoskeleton and cytoskeleton (LINC) complex that connects the nucleus to the cytoplasm, bound to TC-DSBs. The team also found that NUP153 of the nuclear pore complex (NPC), involved in molecular transport between the nucleus and cytoplasm, was required to tether TC-DSBs to the nuclear envelope. PER2 depletion and phases of low PER2 expression in the circadian cycle in cells showed that PER2 is required for SUN1- and NUP153-dependent relocation of TC-DSBs to the nuclear envelope. The tethering of TC-DSBs to the nuclear envelope led to the recruitment of RAD51 on TC-DSBs, promoting homologous recombination repair.
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Nature Chemical Biology https://www.nature.com/nchembio/
Gene Chong
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- Gene Chong
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Correspondence to Gene Chong.
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Chong, G. Clocking in for DNA repair. Nat Chem Biol (2025). https://doi.org/10.1038/s41589-025-02120-x
Published: 22 December 2025
Version of record: 22 December 2025
DOI: https://doi.org/10.1038/s41589-025-02120-x