Caruso Lisa B, Martin Kayla A, Lauretti Elisabetta, Hulse Michael, Siciliano Micheal, Lupey-Green Lena N, Abraham Aaron, Skorski Tomasz, Tempera Italo
Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Present address: The Wistar Institute, Philadelphia, PA, USA.
Oncotarget. 2018 Jan 24;9(12):10585-10605. doi: 10.18632/oncotarget.24291. eCollection 2018 Feb 13.
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 . 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.
聚（ADP - 核糖）聚合酶1（PARP1）在DNA损伤反应中起着非常重要的作用，但其在众多方面的作用尚未完全明确。我们最近发现，在没有DNA损伤的情况下，PARP1可调节染色质修饰酶EZH2的表达。其他研究小组的工作表明，EZH2参与DNA损伤反应。这些综合数据表明，在未处理和经基因毒性剂处理的条件下，EZH2都可能是PARP1的作用靶点。在本研究中，我们验证了一个假设，即响应DNA损伤时，PARP1调节EZH2的活性。在此我们报告，DNA损伤后PARP1调节EZH2的活性。具体而言，我们发现，在细胞中诱导烷基化和紫外线诱导的DNA损伤后，EZH2是PARP1的直接靶点。EZH2的聚（ADP - 核糖）化抑制了EZH2组蛋白甲基转移酶（H3K27me）的酶活性。我们在细胞中观察到，DNA烷基化剂诱导PARP1活性会降低EZH2与染色质的结合，组蛋白H3的聚（ADP - 核糖）化降低了EZH2对其靶标组蛋白H3的亲和力。我们的研究结果表明，PARP1和聚（ADP - 核糖）化是EZH2功能的重要调节因子，并将EZH2介导的异染色质形成、DNA损伤和聚（ADP - 核糖）化联系起来。这些发现可能也具有临床意义，因为它们表明EZH2抑制剂可以提高PARP1抑制剂在BRCA1/2缺陷型癌症中的抗肿瘤效果。
