MicroRNAs down-regulate homologous recombination in the G1 phase of cycling cells to maintain genomic stability

Young Eun Choi, Yunfeng Pan, Eunmi Park, Panagiotis A. Konstantinopoulos, Subhajyoti De, Alan D. D'Andrea, Dipanjan Chowdhury

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Homologous recombination (HR) mediated repair of DNA double-strand break (DSB)s is restricted to the post-replicative phases of the cell cycle. Initiation of HR in the G1 phase blocks non-homologous end joining (NHEJ) impairing DSB repair. Execution of HR in G1 cells can lead to the loss-of-heterozygosity (LOH) which is potentially carcinogenic. We conducted a gain-of-function screen to systematically identify miRNAs that regulate HR-mediated DSB repair, and of these miRNAs, miR-1255b, miR-148b*and miR-193b* specifically suppress the HR-pathway in the G1 phase by targeting BRCA1, BRCA2 and RAD51. miR-1255b, miR-148b*and miR-193b* associate with the transcripts of these HR factors via non-canonical binding sites. Mutations in the miRNA binding sites restore the levels of BRCA1, BRCA2 and RAD51 and neutralize the phenotype induced by over-expressing the miRNAs. Inhibiting miR-1255b, miR-148b* and miR-193b* leads to an ectopic increase in expression of BRCA1, BRCA2 and RAD51 specifically in the G1 phase and impedes DSB repair through the initiation of HR. Depletion of CtIP, a BRCA1-associated DNA end resection protein, rescues this phenotype. Furthermore, deletion of miR-1255b or miR-148b* or miR-193b* in independent cohorts of ovarian tumors correlates with significant increase in LOH events/ chromosomal aberrations and BRCA1 expression.

Original languageEnglish (US)
Article numbere02445
JournaleLife
Volume2014
Issue number3
DOIs
StatePublished - Apr 30 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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