Publication Date:
2014-04-30
Description:
Replication fork stalling can promote genomic instability, predisposing to cancer and other diseases. Stalled replication forks may be processed by sister chromatid recombination (SCR), generating error-free or error-prone homologous recombination (HR) outcomes. In mammalian cells, a long-standing hypothesis proposes that the major hereditary breast/ovarian cancer predisposition gene products, BRCA1 and BRCA2, control HR/SCR at stalled replication forks. Although BRCA1 and BRCA2 affect replication fork processing, direct evidence that BRCA gene products regulate homologous recombination at stalled chromosomal replication forks is lacking, due to a dearth of tools for studying this process. Here we report that the Escherichia coli Tus/Ter complex can be engineered to induce site-specific replication fork stalling and chromosomal HR/SCR in mouse cells. Tus/Ter-induced homologous recombination entails processing of bidirectionally arrested forks. We find that the Brca1 carboxy (C)-terminal tandem BRCT repeat and regions of Brca1 encoded by exon 11-two Brca1 elements implicated in tumour suppression-control Tus/Ter-induced homologous recombination. Inactivation of either Brca1 or Brca2 increases the absolute frequency of 'long-tract' gene conversions at Tus/Ter-stalled forks, an outcome not observed in response to a site-specific endonuclease-mediated chromosomal double-strand break. Therefore, homologous recombination at stalled forks is regulated differently from homologous recombination at double-strand breaks arising independently of a replication fork. We propose that aberrant long-tract homologous recombination at stalled replication forks contributes to genomic instability and breast/ovarian cancer predisposition in BRCA mutant cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118467/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118467/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Willis, Nicholas A -- Chandramouly, Gurushankar -- Huang, Bin -- Kwok, Amy -- Follonier, Cindy -- Deng, Chuxia -- Scully, Ralph -- 5T32CA081156/CA/NCI NIH HHS/ -- R01 CA095175/CA/NCI NIH HHS/ -- R01 GM026938/GM/NIGMS NIH HHS/ -- R01 GM043265/GM/NIGMS NIH HHS/ -- R01 GM073894/GM/NIGMS NIH HHS/ -- R01CA095175/CA/NCI NIH HHS/ -- R01GM073894/GM/NIGMS NIH HHS/ -- R21 CA144017/CA/NCI NIH HHS/ -- R21CA144017/CA/NCI NIH HHS/ -- R37 GM026938/GM/NIGMS NIH HHS/ -- R37GM26938/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 26;510(7506):556-9. doi: 10.1038/nature13295. Epub 2014 Apr 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. ; 1] Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Temple University, 1801 North Broad Street, Philadelphia, Pennsylvania 19122, USA (G.C.); Brandeis University, 415 South Street, Waltham, Massachusetts 02453, USA (B.H.); University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA (A.K.). ; Princeton University, 101 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey 08544, USA. ; NIDDK, National Institutes of Health, Building 10, Room 9N105, 10 Center Drive, Bethesda, Maryland 20814, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24776801" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
BRCA1 Protein/chemistry/genetics/*metabolism
;
BRCA2 Protein/genetics/metabolism
;
DNA Breaks, Double-Stranded
;
*DNA Replication
;
Escherichia coli/genetics
;
Escherichia coli Proteins/genetics/*metabolism
;
Exons/genetics
;
Gene Conversion/genetics
;
Genomic Instability/genetics
;
Hereditary Breast and Ovarian Cancer Syndrome/genetics
;
*Homologous Recombination
;
Mice
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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