荷兰伊拉斯谟癌症研究所Nitika Taneja小组的研究发现复制应激诱导的染色质环保护分叉的稳定性。相关论文于2026年7月1日发表在《自然》杂志上。

研究组发现复制应激诱导瞬时染色质环的形成，该环包围了新的富含异染色质的停滞复制叉。应力分叉优先在收敛的CTCF基序处停止，触发应力依赖的CTCF富集，从而限制环的伸出并稳定这些结构。环的稳定需要CTCF锚定和G9a依赖的异染色质（组蛋白H3的Lys9的三甲基化（H3K9me3））沉积在环体内的新生DNA上。这些环起到保护支架的作用，保护停滞和逆转的叉免受多种核酸酶的降解。

相比之下，应力诱导的异染色质和CTCF富集的联合缺失会破坏环支架的稳定性，暴露出多个核分解攻击的入口点，并通过不同于经典分叉逆转依赖途径的机制导致广泛的新生链降解。这种保护性结构在BRCA2缺陷细胞中同样至关重要，在BRCA2缺陷细胞中，复制应激相关环主要保护复制起始区，而这些环外的新生DNA经历了大规模降解，并且仍然高度易受突变的影响。他们的研究阐明了复制应激诱导的三维基因组重组在保持复制叉稳定性方面的基本作用，从而减轻突变和基因组不稳定性。

据介绍，复制应激对基因组完整性构成重大威胁，但高阶染色质组织如何促进复制叉保护仍不清楚。

附：英文原文

Title: Replication-stress-induced chromatin loops protect fork stability

Author: Gaggioli, Vincent, Sengupta, Kaustav, Choudhury, Ashutosh, Paulson, Joanna, Kuthethur, Raviprasad, Bakker, Collin, Li, Jialun, Lo, Calvin S. Y., Whale, Alex, van den Berg, Jeroen, Asua Intxausti, Leire, Gil-Lanza, Noelia, Galvn-Femena, Ivn, Manolika, Eleni Maria, Eswaran, Sangavi, Khan, Hina N., Ferr, Estel, Stik, Gregorie, van Oudenaarden, Alexander, Papantonis, Argyris, Houseley, Jonathan, Sridharan, Sriram, Chaudhuri, Arnab Ray, Bayona-Feliu, Aleix, Taneja, Nitika

Issue&Volume: 2026-07-01

Abstract: Replication stress poses a major threat to genome integrity, yet how higher-order chromatin organization contributes to replication fork protection remains unclear1,2. Here we show that replication stress induces the formation of transient chromatin loops that enclose de novo heterochromatin-enriched stalled replication forks3. Stressed forks preferentially stall at convergent CTCF motifs, triggering stress-dependent CTCF enrichment that constrains loop extrusion and stabilizes these structures. Loop stabilization requires both CTCF anchoring and G9a-dependent heterochromatin (trimethylation of Lys9 of histone H3 (H3K9me3)) deposition on nascent DNA within the loop body. These loops function as protective scaffolds that shield stalled and reversed forks from degradation by multiple nucleases. By contrast, combined loss of stress-induced heterochromatin and CTCF enrichment destabilizes the loop scaffold, exposing multiple entry points for nucleolytic attack and resulting in extensive nascent-strand degradation through mechanisms distinct from classical fork-reversal-dependent pathways. This protective architecture is similarly critical in BRCA2-deficient cells, in which replication-stress-associated loops predominantly safeguard replication initiation zones, while nascent DNA outside these loops undergoes massive degradation and remains highly susceptible to mutations. Our study elucidates the fundamental role of replication-stress-induced three-dimensional genome reorganization in preserving replication fork stability, thereby mitigating mutagenesis and genomic instability.

DOI: 10.1038/s41586-026-10695-1

Source: https://www.nature.com/articles/s41586-026-10695-1

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504

官方网址：http://www.nature.com/

投稿链接：http://www.nature.com/authors/submit_manuscript.html