DDX39A resolves replication fork-associated RNA-DNA hybrids to balance fork protection and cleavage for genomic stability maintenance

IF 14.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cell Pub Date : 2024-12-19 DOI:10.1016/j.molcel.2024.11.029
Zhanzhan Xu, Chen Nie, Junwei Liao, Yujie Ma, Xiao Albert Zhou, Xiaoman Li, Shiwei Li, Haodong Lin, Yefei Luo, Kaiqi Cheng, Zuchao Mao, Lei Zhang, Yichen Pan, Yuke Chen, Weibin Wang, Jiadong Wang
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引用次数: 0

Abstract

Safeguarding replication fork stability in transcriptionally active regions is crucial for precise DNA replication and mutation prevention. Here, we discover the pervasive existence of replication fork-associated RNA-DNA hybrids (RF-RDs) in transcriptionally active regions of human cells. These hybrids function as protective barriers, preventing DNA2-mediated nascent DNA degradation and replication fork collapse under replication stress. We also identify DDX39A as a RAD51-associated protein that binds to stalled forks and resolves RF-RDs, facilitating proper DNA2-mediated DNA resection and replication fork restart. Excessive dissolution of RF-RDs causes replication fork collapse and genomic instability, while insufficient dissolution of RF-RDs under replication stress increases fork stability, resulting in chemoresistance that can be reversed by eliminating RF-RDs. In summary, we elucidated the prevalence of RF-RDs at replication forks within transcriptionally active regions, revealed their pivotal role in safeguarding replication fork stability, and proposed that targeting RF-RDs holds promise for augmenting chemotherapeutic efficacy.

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来源期刊
Molecular Cell
Molecular Cell 生物-生化与分子生物学
CiteScore
26.00
自引率
3.80%
发文量
389
审稿时长
1 months
期刊介绍: Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.
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