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动态从头组装和拆卸复制叉处的异染色质可确保叉稳定。

Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability.

机构信息

Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

Oncode Institute, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

出版信息

Nat Cell Biol. 2023 Jul;25(7):1017-1032. doi: 10.1038/s41556-023-01167-z. Epub 2023 Jul 6.

DOI:10.1038/s41556-023-01167-z
PMID:37414849
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10344782/
Abstract

Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.

摘要

当 DNA 复制叉受到挑战时，染色质会动态重组。然而，组蛋白修饰的重排过程及其对叉稳定性的影响还知之甚少。在这里，我们发现了一个受检查点调控的染色质信号级联反应，该反应激活组蛋白甲基转移酶 EHMT2/G9a，在受到压力的复制叉上催化异染色质组装。通过生化和单分子染色质纤维方法，我们表明 G9a 与 SUV39h1 一起通过在受压力的复制叉附近积累抑制性修饰 H3K9me1/me2/me3 来诱导染色质紧缩。这种封闭构象也有利于 G9a 依赖性排斥 H3K9 去甲基化酶 JMJD1A/KDM3A，后者有利于叉重新启动时异染色质的解体。KDM3A 从受压力的叉上过早地解聚异染色质，使 PRIMPOL 能够进入，引发单链 DNA 缺口形成，并使细胞对化疗药物敏感。这些发现可能有助于解释在癌症患者中观察到的化疗耐药性和预后不良，这些患者的 G9a/H3K9me3 水平升高。

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