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.
Human subjects: The clinical data from patients was obtained via published sources which include the Cancer Genome Atlas
- Timothy Nilsen, Case Western Reserve University, United States
© 2014, Choi et al.
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