Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Cancer Res. 2012 Aug 15;72(16):4037-46. doi: 10.1158/0008-5472.CAN-12-0103. Epub 2012 Jul 3.
Cell survival after DNA damage relies on DNA repair, the abrogation of which causes genomic instability. The DNA repair protein RAD51 and the trans-lesion synthesis DNA polymerase REV1 are required for resistance to DNA interstrand cross-linking agents such as cisplatin. In this study, we show that overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage. MiR-96 directly targeted the coding region of RAD51 and the 3'-untranslated region of REV1. Overexpression of miR-96 decreased the efficiency of homologous recombination and enhanced sensitivity to the PARP inhibitor AZD2281 in vitro and to cisplatin both in vitro and in vivo. Taken together, our findings indicate that miR-96 regulates DNA repair and chemosensitivity by repressing RAD51 and REV1. As a therapeutic candidate, miR-96 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage.
细胞在 DNA 损伤后的存活依赖于 DNA 修复，而 DNA 修复的缺失会导致基因组不稳定。DNA 修复蛋白 RAD51 和跨损伤合成 DNA 聚合酶 REV1 对于抵抗 DNA 交联剂（如顺铂）是必需的。在这项研究中，我们表明，人癌细胞中 miR-96 的过表达降低了 RAD51 和 REV1 的水平，并影响了细胞对引起 DNA 损伤的药物的反应。miR-96 直接靶向 RAD51 的编码区和 REV1 的 3'-非翻译区。miR-96 的过表达降低了同源重组的效率，并增强了体外对 PARP 抑制剂 AZD2281 和体内对顺铂的敏感性。总之，我们的研究结果表明，miR-96 通过抑制 RAD51 和 REV1 来调节 DNA 修复和化疗敏感性。作为一种治疗候选物，miR-96 可能通过增加癌细胞对 DNA 损伤的敏感性来提高化疗疗效。
