Poly(ADP-ribose) Polymerase 1, PARP1, modifies EZH2 and inhibits EZH2 histone methyltransferase activity after DNA damage.
Poly(ADP-ribose) Polymerase 1, PARP1, modifies EZH2 and inhibits EZH2 histone methyltransferase activity after DNA damage.
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DOI：
10.18632/oncotarget.24291
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发表时间：
2018-02-13
期刊：
影响因子：
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通讯作者：
Tempera I
中科院分区：
文献类型：
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作者：
Caruso LB;Martin KA;Lauretti E;Hulse M;Siciliano M;Lupey-Green LN;Abraham A;Skorski T;Tempera I
聚腺苷二磷酸核糖聚合酶1（PARP 1）在DNA损伤反应中起着非常重要的作用，但其在许多方面的作用尚未完全了解。我们最近发现，在没有DNA损伤的情况下，PARP 1调节染色质修饰酶EZH 2的表达。其他研究小组的工作表明，EZH 2参与了DNA损伤反应。这些综合数据表明，EZH 2可能是PARP 1在未处理和遗传毒性剂处理条件下的靶标。在这项工作中，我们测试的假设，在响应DNA损伤，PARP 1调节EZH 2活性。在这里，我们报告说，PARP 1调节EZH 2活性后，DNA损伤。特别是，我们发现EZH 2是PARP 1在细胞和体外诱导烷基化和UV诱导的DNA损伤后的直接靶点。EZH 2的PAR化抑制EZH 2组蛋白甲基转移酶（H3 K27 me）酶活性。我们在细胞中观察到，DNA烷化剂对PARP 1活性的诱导降低了EZH 2与染色质的结合，组蛋白H3的PAR化降低了EZH 2对其靶组蛋白H3的亲和力。我们的研究结果表明，PARP 1和PAR化是EZH 2功能的重要调节因子，并将EZH 2介导的异染色质形成、DNA损伤和PAR化联系起来。这些发现也可能具有临床意义，因为它们表明EZH 2抑制剂可以改善PARP 1抑制剂在BRCA 1/2缺陷癌症中的抗肿瘤作用。
The enzyme Poly(ADP-ribose) polymerase 1 (PARP1) plays a very important role in the DNA damage response, but its role in numerous aspects is not fully understood. We recently showed that in the absence of DNA damage, PARP1 regulates the expression of the chromatin-modifying enzyme EZH2. Work from other groups has shown that EZH2 participates in the DNA damage response. These combined data suggest that EZH2 could be a target of PARP1 in both untreated and genotoxic agent-treated conditions. In this work we tested the hypothesis that, in response to DNA damage, PARP1 regulates EZH2 activity. Here we report that PARP1 regulates EZH2 activity after DNA damage. In particular, we find that EZH2 is a direct target of PARP1 upon induction of alkylating and UV-induced DNA damage in cells and in vitro. PARylation of EZH2 inhibits EZH2 histone methyltransferase (H3K27me) enzymatic activity. We observed in cells that the induction of PARP1 activity by DNA alkylating agents decreases the association of EZH2 with chromatin, and PARylation of histone H3 reduces EZH2 affinity for its target histone H3. Our findings establish that PARP1 and PARylation are important regulators of EZH2 function and link EZH2-mediated heterochromatin formation, DNA damage and PARylation. These findings may also have clinical implications, as they suggest that inhibitors of EZH2 can improve anti-tumor effects of PARP1 inhibitors in BRCA1/2-deficient cancers.