Rivera M, Wu Q, Hamerlik P, Hjelmeland A B, Bao S, Rich J N
1] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA [2] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Cell Death Dis. 2015 Apr 23;6(4):e1732. doi: 10.1038/cddis.2015.75.
Glioblastoma (GBM), the most prevalent type of primary intrinsic brain cancer in adults, remains universally fatal despite maximal therapy, including radiotherapy and chemotherapy. Cytotoxic therapy generates double-stranded DNA breaks (DSBs), most commonly repaired by homologous recombination (HR). We hypothesized that cancer cells coopt meiotic repair machinery as DSBs are generated during meiosis and repaired by molecular complexes distinct from genotoxic responses in somatic tissues. Indeed, we found that gliomas express meiotic repair genes and their expression informed poor prognosis. We interrogated the function of disrupted meiotic cDNA1 (DMC1), a homolog of RAD51, the primary recombinase used in mitotic cells to search and recombine with the homologous DNA template. DMC1, whose only known function is as an HR recombinase, was expressed by GBM cells and induced by radiation. Although targeting DMC1 in non-neoplastic cells minimally altered cell growth, DMC1 depletion in GBM cells decreased proliferation, induced activation of CHK1 and expression of p21CIP1/WAF1, and increased RPA foci, suggesting increased replication stress. Combining loss of DMC1 with ionizing radiation inhibited activation of DNA damage responses and increased radiosensitivity. Furthermore, loss of DMC1 reduced tumor growth and prolonged survival in vivo. Our results suggest that cancers coopt meiotic genes to augment survival under genotoxic stress, offering molecular targets with high therapeutic indices.
胶质母细胞瘤（GBM）是成人中最常见的原发性脑内癌症类型，尽管采用了包括放疗和化疗在内的最大程度治疗，但其仍然普遍致命。细胞毒性疗法会产生双链DNA断裂（DSB），最常见的是通过同源重组（HR）进行修复。我们推测，癌细胞会利用减数分裂修复机制，因为在减数分裂过程中会产生DSB，并由不同于体细胞组织中基因毒性反应的分子复合物进行修复。事实上，我们发现胶质瘤表达减数分裂修复基因，且它们的表达预示着预后不良。我们研究了破坏的减数分裂cDNA1（DMC1）的功能，DMC1是RAD51的同源物，RAD51是有丝分裂细胞中用于搜索同源DNA模板并与之重组的主要重组酶。DMC1唯一已知的功能是作为HR重组酶，它由GBM细胞表达并受辐射诱导。虽然在非肿瘤细胞中靶向DMC1对细胞生长的影响最小，但在GBM细胞中耗尽DMC1会降低增殖，诱导CHK1激活和p21CIP1/WAF1表达，并增加RPA病灶，提示复制应激增加。将DMC1缺失与电离辐射相结合会抑制DNA损伤反应的激活并增加放射敏感性。此外，DMC1缺失会降低体内肿瘤生长并延长生存期。我们的结果表明，癌症会利用减数分裂基因来增强在基因毒性应激下的生存能力，从而提供具有高治疗指数的分子靶点。
