EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation
EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation
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DOI：
10.1038/ncb3626
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发表时间：
2017-11-01
影响因子：
21.3
通讯作者：
D'Andrea, Alan D.
中科院分区：
文献类型：
--
作者：
Rondinelli, Beatrice;Gogola, Ewa;D'Andrea, Alan D.
对聚adp核糖聚合酶抑制剂（PARPi）耐药的出现对BRCA1和BRCA2 （BRCA1/2）缺陷肿瘤的治疗构成威胁(1)。停滞的DNA复制叉的稳定是最近发现的parpi耐药机制，它促进了brca1 /2缺陷癌症的基因组稳定性(2)。解剖控制停滞分叉的基因组稳定性的分子途径至关重要。在这里，我们发现EZH2定位于停顿叉，在那里它甲基化组蛋白3 （H3K27me3）上的Lys27，介导MUS81核酸酶的募集。低EZH2水平降低H3K27甲基化，阻止停滞分叉处MUS81的募集，并导致分叉稳定。因此，EZH2/MUS81轴功能的丧失促进了brca2缺陷细胞中PARPi的耐药。因此，低EZH2或MUS81表达水平预测brca2突变肿瘤患者的化疗耐药和不良预后。此外，在小鼠Brca2（-/-）乳腺肿瘤模型中，Ezh2的抑制与获得性PARPi抗性有关。我们的研究结果确定EZH2是停滞分叉基因组稳定性的关键调节因子，将组蛋白修饰与核酸酶募集结合在一起。我们的数据确定EZH2表达是brca2缺陷肿瘤对化疗反应的生物标志物。
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(1). Stabilization of stalled DNA replication forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers(2). 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.