A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability
Katerina D. Fagan‐Solis, Dennis A. Simpson, Rashmi J. Kumar, Luciano G. Martelotto, Lisle E. Mose, Naim U. Rashid, Alice Y. Ho, Simon N. Powell, Yuetao Wen, Joel S. Parker, Jorge S. Reis‐Filho, John H.J. Petrini, Gaorav P. Gupta
Abstract
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.