MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress
MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress
复制标题
DOI：
10.1158/0008-5472.can-17-1355
复制
发表时间：
2017-10-01
期刊：
影响因子：
11.2
通讯作者：
Ferguson, David O.
中科院分区：
文献类型：
--
作者：
Spehalski, Elizabeth;Capper, Kayla M.;Ferguson, David O.
编码MRE11/RAD50/NBS1 (MRN) DNA修复复合体的基因的亚形态突变导致癌症易感综合征。MRN结合DNA双链断裂，在修复中起作用，并通过激活共济失调-毛细血管扩张突变激酶触发细胞周期检查点。为了了解MRN在癌症中的作用，我们设计了B淋巴细胞缺乏MRN或携带MRE11缺乏核酸酶活性的MRN的小鼠。MRN缺乏的两种形式导致癌症的标志，包括致癌易位涉及c-Myc和免疫球蛋白位点。这些肿瘤前B淋巴细胞不会发展为可检测的B系淋巴瘤，即使在缺乏p53的情况下。此外，在自发性b细胞淋巴瘤的小鼠模型中，Mre11缺陷阻止了肿瘤的发生。我们的研究结果表明，MRN不能被认为是标准的肿瘤抑制因子，相反，MRE11的核酸酶活性是肿瘤发生所必需的。抑制MRE11核酸酶活性可增加过表达癌基因细胞的DNA损伤并选择性诱导细胞凋亡，提示MRE11在对抗癌基因诱导的复制应激中发挥重要作用。因此，MRE11可能为癌症治疗发展提供一个靶点。更广泛地说，我们的工作支持这样一种观点，即内源性基因组不稳定性的细微增强可以超过癌细胞的耐受性，并被用于治疗目的。AACR (C) 2017。
Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double-strand breaks, where it functions in repair and triggers cell-cycle checkpoints via activation of the ataxia-telangiectasia mutated kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus. These preneoplastic B lymphocytes did not progress to detectable B lineage lymphoma, even in the absence of p53. Moreover, Mre11 deficiencies prevented tumorigenesis in a mouse model strongly predisposed to spontaneous B-cell lymphomas. Our findings indicate that MRN cannot be considered a standard tumor suppressor and instead imply that nuclease activities of MRE11 are required for oncogenesis. Inhibition of MRE11 nuclease activity increased DNA damage and selectively induced apoptosis in cells overexpressing oncogenes, suggesting MRE11 serves an important role in countering oncogene-induced replication stress. Thus, MRE11 may offer a target for cancer therapeutic development. More broadly, our work supports the idea that subtle enhancements of endogenous genome instability can exceed the tolerance of cancer cells and be exploited for therapeutic ends. (C)2017 AACR.