MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)17438-17443
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number35
DOIs
StatePublished - Aug 27 2019

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BRCA1 Protein
Genetic Translocation
DNA End-Joining Repair
Neoplasms
Homologous Recombination
DNA Repair
Recombinational DNA Repair
Genomic Instability
Synthetic Lethal Mutations
MicroRNAs
Poly (ADP-Ribose) Polymerase-1
Therapeutics

Keywords

  • DNA repair
  • MicroRNA
  • Oncogenesis
  • Replication fork

ASJC Scopus subject areas

  • General

Cite this

Srinivasan, G., Williamson, E. A., Kong, K., Jaiswal, A. S., Huang, G., Kim, H. S., ... Hromas, R. (2019). MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers. Proceedings of the National Academy of Sciences of the United States of America, 116(35), 17438-17443. https://doi.org/10.1073/pnas.1903150116

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 35, 27.08.2019, p. 17438-17443.

Research output: Contribution to journalArticle

Srinivasan, G, Williamson, EA, Kong, K, Jaiswal, AS, Huang, G, Kim, HS, Schärer, O, Zhao, W, Burma, S, Sung, P & Hromas, R 2019, 'MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 35, pp. 17438-17443. https://doi.org/10.1073/pnas.1903150116
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. / MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 35. pp. 17438-17443.
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