A P53-independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability. Mus musculus strain:Not Applicable | isolate:Not Applicable | breed:Not Applicable | cultivar:Not Applicable

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 novel 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 ATR and 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.