| First Author | Fagan-Solis KD | Year | 2020 |
| Journal | Cell Rep | Volume | 30 |
| Issue | 5 | Pages | 1385-1399.e7 |
| PubMed ID | 32023457 | Mgi Jnum | J:288080 |
| Mgi Id | MGI:6415931 | Doi | 10.1016/j.celrep.2020.01.020 |
| Citation | Fagan-Solis KD, et al. (2020) A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability. Cell Rep 30(5):1385-1399.e7 |
| abstractText | The Mre11-Rad50-Nbs1 complex is a DNA double-strand break sensor that mediates a tumor-suppressive DNA damage response (DDR) in cells undergoing oncogenic stress, yet the mechanisms underlying this effect are poorly understood. Using a genetically inducible primary mammary epithelial cell model, we demonstrate that Mre11 suppresses proliferation and DNA damage induced by diverse oncogenic drivers through a p53-independent mechanism. Breast tumorigenesis models engineered to express a hypomorphic Mre11 allele exhibit increased levels of oncogene-induced DNA damage, R-loop accumulation, and chromosomal instability with a characteristic copy number loss phenotype. Mre11 complex dysfunction is identified in a subset of human triple-negative breast cancers and is associated with increased sensitivity to DNA-damaging therapy and inhibitors of ataxia telangiectasia and Rad3 related (ATR) and poly (ADP-ribose) polymerase (PARP). Thus, deficiencies in the Mre11-dependent DDR drive proliferation and genome instability patterns in p53-deficient breast cancers and represent an opportunity for therapeutic exploitation. |
