A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability

Abstract

SummaryThe 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 mammary epithelial cell model, we demonstrate that Mre11 suppresses proliferation and DNA damage induced by diverse oncogenic drivers through a p53-independent mechanism. Expression of a hypomorphic mutant allele of Mre11 exacerbates oncogene-driven increases in R-loops and results in a copy number loss phenotype enriched in gene-coding regions that is revealed by whole genome sequencing of mammary hyperplasia and breast tumors. 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.