1. Chromosomes and Gene Expression
Download icon

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

  1. Young Eun Choi
  2. Yunfeng Pan
  3. Eunmi Park
  4. Panagiotis Konstantinopoulos
  5. Subhajyoti De
  6. Alan D'Andrea
  7. Dipanjan Chowdhury  Is a corresponding author
  1. Dana-Farber Cancer Institute, Harvard Medical School, United States
  2. University of Colorado School of Medicine, United States
Research Article
  • Cited 36
  • Views 2,296
  • Annotations
Cite this article as: eLife 2014;3:e02445 doi: 10.7554/eLife.02445

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.

Article and author information

Author details

  1. Young Eun Choi

    Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yunfeng Pan

    Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Eunmi Park

    Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Panagiotis Konstantinopoulos

    Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Subhajyoti De

    University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alan D'Andrea

    Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Dipanjan Chowdhury

    Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    For correspondence
    dipanjan_chowdhury@dfci.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: The clinical data from patients was obtained via published sources which include the Cancer Genome Atlas

Reviewing Editor

  1. Timothy Nilsen, Case Western Reserve University, United States

Publication history

  1. Received: February 2, 2014
  2. Accepted: April 29, 2014
  3. Accepted Manuscript published: April 30, 2014 (version 1)
  4. Version of Record published: May 27, 2014 (version 2)

Copyright

© 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.

Metrics

  • 2,296
    Page views
  • 290
    Downloads
  • 36
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Daniel Andergassen et al.
    Short Report
    1. Chromosomes and Gene Expression
    2. Immunology and Inflammation
    Kevin W Ng et al.
    Research Article