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

Authors: Fagan-Solis, Katerina D; Simpson, Dennis A; Kumar, Rashmi J; Martelotto, Luciano G; Mose, Lisle E; Rashid, Naim U; Ho, Alice Y; Powell, Simon N; Wen, Y Hannah; Parker, Joel S; Reis-Filho, Jorge S; Petrini, John H J; Gupta, Gaorav P

Published In Cell Rep, (2020 02 04)

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.

PubMed ID: 32023457

MeSH Terms: No MeSH terms associated with this publication