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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 +3 more·2019·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1903150116PMC PMC6717293
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Abstract

Significance: One origin of cancer arises from defects in the homologous recombination (HR) DNA repair pathway, which results in oncogenic genomic instability. Normal cells prefer HR for repair of stressed replication forks because it is highly conservative. The back-up pathway for repair of stressed replication forks, alternative non-homologous end-joining (aNHEJ), can result in chromosomal instability. Normal cells use microRNA (miR) 223-3p to down-regulate aNHEJ and thus promote HR, which protects genomic stability. However, those cancers that arise from inherited or acquired defects in HR components, such as the BRCA1 breast and ovarian cancers, silence miR223-3p to enhance aNHEJ repair of stressed replication forks. Reconstituting expression of miR223-3p in these cancers causes synthetic lethality, and is a potential therapeutic modality.

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  • Cancer cells lacking BRCA1 and BAP1, which are deficient in homologous recombination, aberrantly express high levels of miR-223* (5p).

    “Cancer cells lacking BRCA1 (breast cancer 1) and BAP1 (BRCA1‐associated protein), which are deficient in homologous recombination, aberrantly express high levels of miR‐223* (5p) (Srinivasan et al., 2019; Figure 6b, Table 1).”

    From microRNA strand selection: Unwinding the rules (2021) · cites this paper as Srinivasan et al., 2019

  • Restoration of miR-223 (3p) in BRCA1, BAP1-deficient cancer cells is synthetic lethal, probably due to repression of NHEJ components.

    “Consistently, restoration of miR‐223 (3p) in BRCA1, BAP1‐deficient cancer cells is synthetic lethal, probably due to repression of NHEJ components (Srinivasan et al., 2019).”

    From microRNA strand selection: Unwinding the rules (2021) · cites this paper as Srinivasan et al., 2019

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Cited by

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Authors
Srinivasan, G., Williamson, E. A., Kong, K., Jaiswal, A. S., Huang, G., Kim, H.-S., Schärer, O., Zhao, W., Burma, S., Sung, P., & Hromas, R.
Affiliations
  • Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229;
  • Center for Genomic Integrity, Institute for Basic Science, Ulsan 689-798, Republic of Korea;
  • Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229;
ORCID
Hromas, Robert
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2019-08-08
Volume
116
Issue
35
Pages
17438-17443
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.1903150116
PMC
PMC6717293
Cited by
30
References
2
Language
en
Update notices
correction (2020-04-06)
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Funders
  • HHS | National Institutes of Health (RO1 CA197796, RO1 ES007061, GM109645, CA205224, CA220123)
  • Korea Institute of Science and Technology (IBS-R022-A1-2017)

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