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

• 成果类型: Article
• 署名作者: Sebastian, Robin; Sun, Eric G.; Fedkenheuer, Michael; Fu, Haiqing; Jung, Seolkyoung; Thakur, Bhushan L.; Redon, Christophe E.; Pegoraro, Gianluca; Tran, Andy D.; Gross, Jacob M.; Mosavarpour, Sara; Kusi, Nana Afua; Ray, Anagh; Dhall, Anjali; Pongor, Lorinc S.; Casellas, Rafael; Aladjem, Mirit I.
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS); National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Cornell University; Weill Cornell Medicine; Rockefeller University; Memorial Sloan Kettering Cancer Center; University of Texas System; UTMD Anderson Cancer Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3337
• DOI: 10.1038/s41586-024-08557-9
• 发表日期: 2025-03-27
• 关键词: read alignment; genome; cohesin; protein; damage; atm; phosphorylation; transcription; complex; repair

摘要

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, 4-5. These observations reveal a previously unknown vulnerability in the DNA replication machinery that may be exploited to therapeutically target cancer cells.