ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer
ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer
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DOI：
10.1016/j.canlet.2022.01.013
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发表时间：
2022-01-20
期刊：
影响因子：
9.7
通讯作者：
Cao, Liping
中科院分区：
文献类型：
--
作者：
Huang, Chaojie;Zhou, Senhao;Cao, Liping
DNA损伤修复是胰腺导管腺癌（PDAC）化疗疗效的主要障碍，包括铂类和吉西他滨/白蛋白结合型紫杉醇治疗的疗效。N6-甲基腺苷修饰（m（6）A）最近被报道在DNA双链断裂（DSB）的同源重组（HR）修复中起作用;然而，其作用机制仍然未知。我们的前期工作表明，非瑟酮可能是一个有前途的抗肿瘤药物，诱导DNA损伤。在本研究中，我们报道了非瑟酮通过m（6）A修饰诱导PDAC细胞的DSB并抑制HR修复。m（6）A writer ZC 3 H13和PBAF染色质重塑复合物的亚基PHF 10被鉴定为受非瑟酮处理影响的主要分子。据我们所知，这是首次发现PHF 10并参与DNA损伤反应。PHF 10功能丧失导致γ H2 AX、RAD 51和53 BP 1向DSB位点的募集增加，并降低HR修复效率。此外，ZC 3 H13敲低下调PHF 10的m（6）A甲基化，并以YTHDF 1依赖的方式减少PHF 10的翻译。总之，我们的研究表明，非瑟酮通过ZC 3 H13介导的PHF 10的m（6）A修饰增强DSB，这可能为PDAC的新治疗方法提供见解。
DNA damage repair is a major barrier for chemotherapy efficacy of pancreatic ductal adenocarcinoma (PDAC), including the efficacy of platinum-based and gemcitabine/nab-paclitaxel treatments. N6-methyladenosine modifications (m(6)A) have recently been reported to play a role in homologous recombination (HR) repair of DNA double strand breaks (DSBs); however, the mechanism of action remains unknown. Our previous work indicated that fisetin may be a promising anti-tumour agent that induces DNA damage. In this study, we reported that fisetin induced DSBs and suppressed HR repair through m(6)A modification in PDAC cells. The m(6)A writer ZC3H13 and PHF10, which is a subunit of the PBAF chromatin remodelling complex, were identified as the main molecules affected by fisetin treatment. To our knowledge, it's the first time that PHF10 was found and involved in the DNA damage response. PHF10 loss-of-function resulted in elevated recruitment of gamma H2AX, RAD51, and 53BP1 to DSB sites and decreased HR repair efficiency. Moreover, ZC3H13 knockdown downregulated the m(6)A methylation of PHF10 and decreased PHF10 translation in a YTHDF1-dependent manner. In conclusion, our study demonstrates that fisetin enhanced DSBs via ZC3Hl3-mediated m(6)A modification of PHF10, which may provide insight into novel therapeutic approaches for PDAC.