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

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.

Cell reports (Cambridge), 2020-02, Vol.30 (5), p.1385-1399.e7 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability
Autor: 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.
Assuntos: Animals ; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins - metabolism ; breast cancer ; Breast Neoplasms - pathology ; Carcinogenesis - pathology ; Cell Line, Tumor ; Cell Proliferation ; Cells, Cultured ; Chromosomal Instability ; DNA Damage ; DNA damage response ; Epithelial Cells - metabolism ; Gene Dosage ; genome instability ; Genomic Instability ; genomic scar ; HEK293 Cells ; Humans ; Mammary Glands, Animal - pathology ; Mice ; Models, Biological ; Mre11 ; MRE11 Homologue Protein - metabolism ; Oncogenes ; oncogenic stress ; Phenotype ; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology ; R loops ; R-Loop Structures ; replication stress ; Tumor Suppressor Protein p53 - metabolism
É parte de: Cell reports (Cambridge), 2020-02, Vol.30 (5), p.1385-1399.e7
Notas: AUTHOR CONTRIBUTIONS
Conceptualization, G.P.G. and J.H.J.P.; Methodology, G.P.G.; Software, D.A.S. and L.E.M.; Formal Analysis, D.A.S. and N.U.R.; Investigation, K.D.F.- S., D.A.S., R.J.K., L.G.M., and Y.H.W.; Resources, G.P.G., A.Y.H., S.N.P., J.S.P., J.S.R.-F., and J.H.J.P.; Writing - Original Draft, G.P.G., K.D.F.-S. and A.S.; Writing - Review & Editing, all authors; Funding Acquisition, G.P.G., K.D.F.-S., and J.H.J.P.; Supervision, G.P.G.
Descrição: 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. [Display omitted] •Mre11-mediated tumor suppression is p53 independent•Mre11 suppresses DNA damage at oncogene-induced R loops•Breast cancers with Mre11 dysfunction exhibit a genomic loss signature•Mre11 dysfunction induces sensitivity to PARP and ATR inhibitors The origins of genome instability in cancer remain poorly understood. Fagan-Solis et al. reveal a p53-independent genome integrity checkpoint pathway mediated by Mre11 that protects against genome instability in breast cancer. Mre11 dysfunction in breast cancer models induces a genomic loss signature and vulnerability to PARP and ATR inhibitors.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

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.

United States: Elsevier Inc

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