DNA双链断裂末端切除因子和WRN促进人类细胞中的有丝分裂DNA合成。

DNA double-strand break end resection factors and WRN facilitate mitotic DNA synthesis in human cells.

作者信息

Barwacz Szymon A, Lundgaard Katrine, Wu Wei, Richter Philipp H, Ren Liqun, Bhowmick Rahul, Gonçalves Dinis Marisa M, Kanemaki Masato T, Liu Ying

机构信息

Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

MOA Key Laboratory of Animal Virology, Center for Veterinary Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

出版信息

Nat Commun. 2025 Aug 25;16(1):7901. doi: 10.1038/s41467-025-63292-7.

DOI:10.1038/s41467-025-63292-7

PMID:40854910

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12379236/

Abstract

Mitotic DNA synthesis (MiDAS) serves to complete the replication of genomic loci that are not fully replicated in S phase in response to replication stress. Previous studies suggest that MiDAS might proceed via break-induced DNA replication, a sub-pathway of homologous recombination repair activated at broken or collapsed replication forks. We set out to define whether DNA double strand break end-resection factors play a role in MiDAS. Here, we show that several core end-resection factors, including MRE11, CtIP and BRCA1 are essential for MiDAS. In addition, while loss of WRN or DNA2 impairs MiDAS, there is no requirement for other known end-resection factors such as EXO1 and BLM. Moreover, both the exonuclease and the helicase activities of WRN contribute to MiDAS. Because oncogene-induced replication stress is common in cancers, targeting of WRN or other factors required for MiDAS could facilitate the development of targeted cancer therapies.

摘要

有丝分裂DNA合成（MiDAS）用于完成基因组位点的复制，这些位点在S期因复制应激而未完全复制。先前的研究表明，MiDAS可能通过断裂诱导的DNA复制进行，这是同源重组修复的一个子途径，在断裂或塌陷的复制叉处被激活。我们着手确定DNA双链断裂末端切除因子是否在MiDAS中发挥作用。在这里，我们表明几个核心末端切除因子，包括MRE11、CtIP和BRCA1对MiDAS至关重要。此外，虽然WRN或DNA2的缺失会损害MiDAS，但不需要其他已知的末端切除因子，如EXO1和BLM。此外，WRN的核酸外切酶和解旋酶活性都有助于MiDAS。由于癌基因诱导的复制应激在癌症中很常见，靶向WRN或MiDAS所需的其他因子可能有助于开发靶向癌症治疗方法。