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.
Keywords: Genome instability, DNA repair, Tumorigenesis, Oncogene, Proliferation, Breast Cancer
Fagan-Solis, Katerina and Simpson, Dennis A. and Kumar, Rashmi J. and Martelotto, Luciano and Mose, Lisle E. and Rashid, Naim and Ho, Alice Y. and Powell, Simon N. and Wen, Y. Hannah and Parker, Joel S. and Reis-Filho, Jorge S. and Petrini, John and Gupta, Gaorav, A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability (June 14, 2019). Available at SSRN: https://ssrn.com/abstract=3404264 or http://dx.doi.org/10.2139/ssrn.3404264
This version of the paper has not been formally peer reviewed.
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