Mechanism for local attenuation of DNA replication at double-strand breaks

Robin Sebastian, Eric G. Sun, Michael Fedkenheuer, Haiqing Fu, SeolKyoung Jung, Bhushan L. Thakur, Christophe E. Redon, Gianluca Pegoraro, Andy D. Tran, Jacob M. Gross, Sara Mosavarpour, Nana Afua Kusi, Anagh Ray, Anjali Dhall, Lorinc S. Pongor, Rafael Casellas and Mirit I. Aladjem ()
Additional contact information
Robin Sebastian: National Institutes of Health
Eric G. Sun: National Institutes of Health
Michael Fedkenheuer: National Institutes of Health
Haiqing Fu: National Institutes of Health
SeolKyoung Jung: National Institutes of Health
Bhushan L. Thakur: National Institutes of Health
Christophe E. Redon: National Institutes of Health
Gianluca Pegoraro: National Institutes of Health
Andy D. Tran: National Cancer Institute
Jacob M. Gross: National Institutes of Health
Sara Mosavarpour: National Institutes of Health
Nana Afua Kusi: National Institutes of Health
Anagh Ray: National Institutes of Health
Anjali Dhall: National Institutes of Health
Lorinc S. Pongor: National Institutes of Health
Rafael Casellas: National Institutes of Health
Mirit I. Aladjem: National Institutes of Health

Nature, 2025, vol. 639, issue 8056, 1084-1092

Abstract: Abstract DNA double-strand breaks (DSBs) disrupt the continuity of the genome, with consequences for malignant transformation. Massive DNA damage can elicit a cellular checkpoint response that prevents cell proliferation1,2. However, how highly aggressive cancer cells, which can tolerate widespread DNA damage, respond to DSBs alongside continuous chromosome duplication is unknown. Here we show that DSBs induce a local genome maintenance mechanism that inhibits replication initiation in DSB-containing topologically associating domains (TADs) without affecting DNA synthesis at other genomic locations. This process is facilitated by mediators of replication and DSBs (MRDs). In normal and cancer cells, MRDs include the TIMELESS–TIPIN complex and the WEE1 kinase, which actively dislodges the TIMELESS–TIPIN complex from replication origins adjacent to DSBs and prevents initiation of DNA synthesis at DSB-containing TADs. Dysregulation of MRDs, or disruption of 3D chromatin architecture by dissolving TADs, results in inadvertent replication in damaged chromatin and increased DNA damage in cancer cells. We propose that the intact MRD cascade precedes DSB repair to prevent genomic instability, which is otherwise observed when replication is forced, or when genome architecture is challenged, in the presence of DSBs3–5. These observations reveal a previously unknown vulnerability in the DNA replication machinery that may be exploited to therapeutically target cancer cells.

Date: 2025
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DOI: 10.1038/s41586-024-08557-9

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