A p53-independent DNA damage response suppresses oncogenic proliferation and genome instability Journal Article

   


Authors: Fagan-Solis, K. D.; Simpson, D. A.; Kumar, R. J.; Martelotto, L. G.; Mose, L. E.; Rashid, N. U.; Ho, A. Y.; Powell, S. N.; Wen, Y. H.; Parker, J. S.; Reis-Filho, J. S.; Petrini, J. H. J.; Gupta, G. P.
Article Title: A p53-independent DNA damage response suppresses oncogenic proliferation and genome instability
Abstract: 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. © 2020 The Authors 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. © 2020 The Authors
Keywords: controlled study; human tissue; unclassified drug; human cell; major clinical study; gene deletion; cisplatin; doxorubicin; nonhuman; paclitaxel; cell proliferation; animal cell; mouse; phenotype; allele; animal tissue; dna damage; mre11; breast cancer; epidermal growth factor receptor 2; animal experiment; animal model; camptothecin; protein p53; cancer inhibition; oncogene; dna; genomic instability; carcinogenicity; gene loss; chromosomal instability; dna damage response; chromosome rearrangement; gene dosage; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; breast carcinogenesis; drug sensitivity; atr protein; cell hyperplasia; protein serine threonine kinase inhibitor; triple negative breast cancer; replication stress; oncogenic stress; human; female; priority journal; article; whole genome sequencing; genome instability; breast epithelium cell; talazoparib; r loops; double strand break repair protein mre11; genomic scar; discoidin domain receptor; ve 821
Journal Title: Cell Reports
Volume: 30
Issue: 5
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2020-02-04
Start Page: 1385
End Page: 1399.e7
Language: English
DOI: 10.1016/j.celrep.2020.01.020
PUBMED: 32023457
PROVIDER: scopus
PMCID: PMC7361372
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85078782854&doi=10.1016%2fj.celrep.2020.01.020&partnerID=40&md5=f9c2e57c0f5f0771c9ce5dde40e43d90
Notes: Article -- Export Date: 2 March 2020 -- Source: Scopus
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MSK Authors
  1. Simon Nicholas Powell
    331 Powell
  2. John Petrini
    94 Petrini
  3. Hannah Yong Wen
    301 Wen
  4. Jorge Sergio Reis-Filho
    639 Reis-Filho
  5. Luciano Gaston Martelotto
    69 Martelotto
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