Acquisition of meiotic DNA repair regulators maintain genome stability in glioblastoma.
Acquisition of meiotic DNA repair regulators maintain genome stability in glioblastoma.
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DOI：
10.1038/cddis.2015.75
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发表时间：
2015-04-23
影响因子：
9
通讯作者：
Rich JN
中科院分区：
文献类型：
--
作者：
Rivera M;Wu Q;Hamerlik P;Hjelmeland AB;Bao S;Rich JN
胶质母细胞瘤（GBM）是成人中最常见的原发性内源性脑癌，尽管进行了最大限度的治疗，包括放疗和化疗，但仍然普遍致命。细胞毒性治疗产生双链DNA断裂（DSB），最常见的是通过同源重组（HR）修复。我们假设癌细胞利用减数分裂修复机制，因为DSB是在减数分裂过程中产生的，并由不同于体细胞组织中遗传毒性反应的分子复合物修复。事实上，我们发现神经胶质瘤表达减数分裂修复基因，它们的表达预示预后不良。我们询问了被破坏的减数分裂cDNA 1（DMC 1）的功能，它是RAD 51的同源物，RAD 51是有丝分裂细胞中用于搜索并与同源DNA模板重组的主要重组酶。DMC 1，其唯一已知的功能是作为HR重组酶，由GBM细胞表达并由辐射诱导。尽管靶向非肿瘤细胞中的DMC 1最小程度地改变了细胞生长，但GBM细胞中的DMC 1消耗降低了增殖，诱导了CHK 1的活化和p21 CIP 1/WAF 1的表达，并增加了RPA病灶，表明复制应激增加。结合DMC 1的损失与电离辐射抑制DNA损伤反应的激活和增加辐射敏感性。此外，DMC 1的缺失减少了肿瘤生长并延长了体内存活。我们的研究结果表明，癌症coopt减数分裂基因，以增加生存的遗传毒性压力下，提供高治疗指数的分子靶点。
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.