Title | MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Spehalski E, Capper KM, Smith CJ, Morgan MJ, Dinkelmann M, Buis J, Sekiguchi JAM, Ferguson DO |
Journal | Cancer Res |
Volume | 77 |
Issue | 19 |
Pagination | 5327-5338 |
Date Published | 2017 10 01 |
ISSN | 1538-7445 |
Keywords | Animals, Apoptosis, Ataxia Telangiectasia Mutated Proteins, ATP-Binding Cassette Transporters, B-Lymphocytes, Cell Cycle Proteins, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, DNA Breaks, Double-Stranded, DNA Repair, DNA Repair Enzymes, DNA Replication, DNA-Binding Proteins, Embryo, Mammalian, Fibroblasts, Genomic Instability, Lymphoma, B-Cell, Mice, MRE11 Homologue Protein, Mutation, Nuclear Proteins, Oncogenes, Proto-Oncogene Proteins c-myc |
Abstract | 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. . |
DOI | 10.1158/0008-5472.CAN-17-1355 |
Alternate Journal | Cancer Res. |
PubMed ID | 28819025 |
PubMed Central ID | PMC5831255 |
Grant List | P30 CA046592 / CA / NCI NIH HHS / United States F31 CA163530 / CA / NCI NIH HHS / United States R01 HL079118 / HL / NHLBI NIH HHS / United States T32 CA009676 / CA / NCI NIH HHS / United States R01 AI063058 / AI / NIAID NIH HHS / United States T32 GM007544 / GM / NIGMS NIH HHS / United States T32 AI007413 / AI / NIAID NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:12pm