MicroRNAs down-regulate homologous recombination in the G1 phase of cycling cells to maintain genomic stability
- Dana-Farber Cancer Institute, Harvard Medical School, United States
- University of Colorado School of Medicine, United States
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. Completion 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 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. These miRNAs target the transcripts of HR factors, BRCA1, BRCA2 and RAD51 and inhibiting miR-1255b, miR-148b*and miR-193b* increases expression of BRCA1/BRCA2/RAD51 specifically in the G1-phase leading to impaired DSB repair. Depletion of CtIP, a BRCA1-associated DNA end resection protein, rescues this phenotype. Furthermore, deletion of miR-1255b, miR-148b*and miR-193b* in independent cohorts of ovarian tumors correlates with significant increase in LOH events/ chromosomal aberrations and BRCA1 expression.
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Human subjects: The clinical data from patients was obtained via published sources which include the Cancer Genome Atlas
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© 2014, Choi et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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MicroRNAs down-regulate homologous recombination in the G1 phase of cycling cells to maintain genomic stability
eLife 3:e02445.
https://doi.org/10.7554/eLife.02445
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