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National Institute of Environmental Health Sciences

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Publication Detail

Title: MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers.

Authors: Srinivasan, Gayathri; Williamson, Elizabeth A; Kong, Kimi; Jaiswal, Aruna S; Huang, Guangcun; Kim, Hyun-Suk; Schärer, Orlando; Zhao, Weixing; Burma, Sandeep; Sung, Patrick; Hromas, Robert

Published In Proc Natl Acad Sci U S A, (2019 08 27)

Abstract: Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223-3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.

PubMed ID: 31395736 Exiting the NIEHS site

MeSH Terms: 3' Untranslated Regions; BRCA1 Protein/deficiency*; Cell Line, Tumor; DNA Repair; DNA Replication; Gene Expression Regulation, Neoplastic; Genetic Association Studies; Genetic Predisposition to Disease*; Genomic Instability; Humans; MicroRNAs/genetics*; Neoplasms/genetics*; Recombinational DNA Repair; Synthetic Lethal Mutations*; Translocation, Genetic

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