MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress

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 (ATM) 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 pre-neoplastic 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.

MRE11 inhibition highlights a replication stress-dependent vulnerability of MYCN-driven tumors

“…Spehalski et al 46 reported that Mre11 deficiency prevented tumorigenesis in mouse p53 −/− B-cell lymphoma models associated with oncogenic translocations involving Myc genes, indicating that MRE11 (and by extension the MRN complex) cannot be considered a standard tumor suppressor since its activity is required for cancer development. In line with this, we have now demonstrated that MRE11 is also required for an efficient RS control and for the survival of preclinical models of established MYCN-driven human cancer.…”

“…It has been recently reported that p53 orchestrates DNA replication restart homeostasis via a transcription- and apoptosis-independent function, by aiding MRE11 recruitment on stalled replication forks to prevent the activity of RAD52/Polθ mutagenic pathways 47 . While it is likely that MRE11 recruitment onto “stressed” forks is strictly connected to its tumor survival functions, data from Spehalski et al 46 imply that p53 is dispensable to this end, since they unveiled MRE11 oncogenic activity in p53 − /− B-cell lymphomas. Further studies will be definitely required to better define the complex relationships between p53 and the MRN complex at the replication forks, in normal and cancer cells.…”

Gene expression profiling reveals a close relationship between follicular lymphoma grade 3A and 3B, but distinct profiles of follicular lymphoma grade 1 and 2

“…Intriguingly, 3 genes, MRE11A, TXN and TOP2A , had already been associated with the pathogenesis of lymphoma and, therefore, targeting their expression might be beneficial for tailored therapy ( Online Supplementary Table S3 ). 24 – 26 …”

Analysis of eEF1Bγ interactome in the nuclear fraction of A549 human lung adenocarcinoma cells

“…Cancer-related functions of PCBP2, TIA-1, HuR/ELAVL1, SERBP1, YTHDC2, YTHDF2 (Mapofthecell database) were described above. All experimentally defined partners of eEF1Bγ picked up by Cytoscape to build molecular networks, are linked to cancer as well [2,[125][126][127][128][129][130][131][132].…”