MicroRNAs down-regulate homologous recombination in the G1 phase of cycling cells to maintain genomic stability.
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.DOI: http://dx.doi.org/10.7554/eLife.02445.001.
Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
Young Eun
YE
Choi
Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
Yunfeng
Y
Pan
Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
Eunmi
E
Park
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
Panagiotis
P
Konstantinopoulos
Department of Medicine, University of Colorado School of Medicine, Aurora, United States.
Subhajyoti
S
De
Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
Alan
A
D'Andrea
Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States dipanjan_chowdhury@dfci.harvard.edu.
Dipanjan
D
Chowdhury
D001483:Base Sequence; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015723:Gene Library; D042822:Genomic Instability; D059765:Homologous Recombination / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059767:Recombinational DNA Repair; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology
D004791:Enzyme Inhibitors; D035683:MicroRNAs; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D011065:Poly(ADP-ribose) Polymerases
BRCA1; DNA repair; cell cycle