The emergence of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) poses a threat to the treatment of BRCA1 and BRCA2 (BRCA1/2)-deficient tumours. Stabilization of stalled DNA replication forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers. Dissecting the molecular pathways controlling genomic stability at stalled forks is critical. Here we show that EZH2 localizes at stalled forks where it methylates Lys27 on histone 3 (H3K27me3), mediating recruitment of the MUS81 nuclease. Low EZH2 levels reduce H3K27 methylation, prevent MUS81 recruitment at stalled forks and cause fork stabilization. As a consequence, loss of function of the EZH2/MUS81 axis promotes PARPi resistance in BRCA2-deficient cells. Accordingly, low EZH2 or MUS81 expression levels predict chemoresistance and poor outcome in patients with BRCA2-mutated tumours. Moreover, inhibition of Ezh2 in a murine Brca2^-/- breast tumour model is associated with acquired PARPi resistance. Our findings identify EZH2 as a critical regulator of genomic stability at stalled forks that couples histone modifications to nuclease recruitment. Our data identify EZH2 expression as a biomarker of BRCA2-deficient tumour response to chemotherapy.

中文翻译：

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EZH2通过组蛋白H3三甲基化募集MUS81，促进停滞的复制叉的降解。

对聚ADP-核糖聚合酶抑制剂（PARPi）的耐药性的出现对BRCA1和BRCA2（BRCA1 / 2）缺陷型肿瘤的治疗构成了威胁。失速的DNA复制叉的稳定化是最近发现的PARPi抗性机制，可促进BRCA1 / 2缺陷型癌症的基因组稳定性。剖析控制失速叉基因组稳定性的分子途径至关重要。在这里，我们显示EZH2定位在停滞的叉子处，在该处它使组蛋白3（H3K27me3）上的Lys27甲基化，从而介导MUS81核酸酶的募集。低EZH2水平可减少H3K27甲基化，防止MUS81在停转的货叉处募集并导致货叉稳定。结果，EZH2 / MUS81轴功能的丧失促进了BRCA2缺陷细胞的PARPi抗性。因此，低EZH2或MUS81表达水平可预测BRCA2突变肿瘤患者的化学耐药性和不良预后。此外，在鼠Brca2中抑制Ezh2^-/-乳腺肿瘤模型与获得性PARPi耐药性相关。我们的发现将EZH2定位为失速叉基因组稳定性的关键调节剂，该蛋白将组蛋白修饰与核酸酶募集相结合。我们的数据确定EZH2表达是BRCA2缺乏化学疗法对肿瘤反应的生物标记。