瑞士苏黎世大学Massimo Lopes团队取得一项新突破。他们的研究发现内聚蛋白重塑复制叉接触，以帮助叉减慢和逆转。该研究于2026年9月16日发表于国际一流学术期刊《自然》杂志上。

DNA复制叉可受到癌症化疗治疗的挑战，导致单链DNA积累和DNA合成减慢。复制压力下复制叉的显著可塑性确保了复制叉稳定性、损伤耐受和完整基因组复制。复制叉的起始和推进发生在三维组织的基因组中。黏连蛋白复合物进行的DNA环挤出组织基因组，并调控DNA复制起点的起始和定位。尽管最近报道了在未受扰动复制过程中姐妹复制叉的瞬时相互作用，但复制压力期间复制叉接触的功能相关性以及黏连蛋白在此背景下的作用仍不清楚。在此，研究人员表明，黏连蛋白介导的环挤出重排了受压力复制叉处的新生DNA接触，以促进基因组稳定性。利用生长素诱导降解子、功能分离突变体以及新开发的基于Micro-C捕获新生DNA处染色质接触的技术（Repli-C），研究人员发现，挤出环的黏连蛋白在停滞的复制叉处积累，限制姐妹复制叉耦合，而有利于复制子间接触。这一过程通过阻止PRIMPOL对单链DNA的作用，促进主动的复制叉减速和逆转。这些发现表明，复制压力反应不仅仅是单个调控事件的累积，而是通过黏连蛋白环挤出在基因组范围内进行拓扑整合。在为挤出环的黏连蛋白提供新功能的同时，研究人员的结果表明肿瘤中频繁的黏连蛋白突变对癌症治疗具有潜在影响。

附：英文原文

Title: Cohesin reshapes replication fork contacts to aid fork slowing and reversal

Author: Gonzlez-Acosta, Daniel, Gimnez-Llorente, Daniel, Rodrigues, Melani, Aouami, Moses, Barroso-Gomila, Orhi, Muoz, Javier, Cuadrado, Ana, Losada, Ana, Lopes, Massimo

Issue&Volume: 2026-09-16

Abstract: DNA replication forks can be challenged by cancer chemotherapeutic treatments, leading to accumulation of single-stranded DNA and slowdown of DNA synthesis. The marked plasticity of replication forks under replication stress ensures fork stability, damage tolerance and complete genome duplication1. Initiation and progression of replication forks occur in a three-dimensionally organized genome. DNA loop extrusion by the cohesin complex organizes the genome2 and regulates the initiation and positioning of DNA replication origins3,4. Although transient interaction of sister forks was recently reported during unperturbed replication5, the functional relevance of fork contacts during replication stress and the role of cohesin in this context remain unknown. Here we show that cohesin-mediated loop extrusion rearranges nascent DNA contacts at stressed replication forks to promote genome stability. Using auxin-inducible degron6, separation-of-function mutants7,8,9 and a newly developed Micro-C-based technique to capture chromatin contacts at nascent DNA (Repli-C), we found that loop-extruding cohesin accumulates at stalled replication forks, limiting sister-fork coupling in favour of inter-replicon contacts. This process promotes active fork slowing and reversal by preventing PRIMPOL action on single-stranded DNA1. These findings show that the replication stress response is not merely an accumulation of individual regulatory events, but is topologically integrated across the genome through cohesin loop extrusion. While providing a new function for loop-extruding cohesin, our results indicate the potential impact on cancer therapy of frequent cohesin mutations in tumours10.

DOI: 10.1038/s41586-026-11034-0

Source: https://www.nature.com/articles/s41586-026-11034-0