The tumor suppressor BRCA1-BARD1 complex localizes to the synaptonemal complex and regulates recombination under meiotic dysfunction in Caenorhabditis elegans.
Autor: | Li Q; Department of Molecular and Cellular Biology, University of California Davis; Davis CA, United States of America., Saito TT; Department of Genetics, Harvard Medical School; Boston, MA, United States of America., Martinez-Garcia M; Department of Genetics, Harvard Medical School; Boston, MA, United States of America., Deshong AJ; Department of Molecular and Cellular Biology, University of California Davis; Davis CA, United States of America., Nadarajan S; Department of Genetics, Harvard Medical School; Boston, MA, United States of America., Lawrence KS; Department of Molecular and Cellular Biology, University of California Davis; Davis CA, United States of America., Checchi PM; Department of Molecular and Cellular Biology, University of California Davis; Davis CA, United States of America., Colaiacovo MP; Department of Genetics, Harvard Medical School; Boston, MA, United States of America., Engebrecht J; Department of Molecular and Cellular Biology, University of California Davis; Davis CA, United States of America. |
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Jazyk: | angličtina |
Zdroj: | PLoS genetics [PLoS Genet] 2018 Nov 01; Vol. 14 (11), pp. e1007701. Date of Electronic Publication: 2018 Nov 01 (Print Publication: 2018). |
DOI: | 10.1371/journal.pgen.1007701 |
Abstrakt: | Breast cancer susceptibility gene 1 (BRCA1) and binding partner BRCA1-associated RING domain protein 1 (BARD1) form an essential E3 ubiquitin ligase important for DNA damage repair and homologous recombination. The Caenorhabditis elegans orthologs, BRC-1 and BRD-1, also function in DNA damage repair, homologous recombination, as well as in meiosis. Using functional GFP fusions we show that in mitotically-dividing germ cells BRC-1 and BRD-1 are nucleoplasmic with enrichment at foci that partially overlap with the recombinase RAD-51. Co-localization with RAD-51 is enhanced under replication stress. As cells enter meiosis, BRC-1-BRD-1 remains nucleoplasmic and in foci, and beginning in mid-pachytene the complex co-localizes with the synaptonemal complex. Following establishment of the single asymmetrically positioned crossover on each chromosome pair, BRC-1-BRD-1 concentrates to the short arm of the bivalent. Localization dependencies reveal that BRC-1 and BRD-1 are interdependent and the complex fails to properly localize in both meiotic recombination and chromosome synapsis mutants. Consistent with a role for BRC-1-BRD-1 in meiotic recombination in the context of the synaptonemal complex, inactivation of BRC-1 or BRD-1 enhances the embryonic lethality of mutants defective in chromosome synapsis. Our data suggest that under meiotic dysfunction, BRC-1-BRD-1 stabilizes the RAD-51 filament and alters the recombination landscape; these two functions can be genetically separated from BRC-1-BRD-1's role in the DNA damage response. Together, we propose that BRC-1-BRD-1 serves a checkpoint function at the synaptonemal complex where it monitors and modulates meiotic recombination. Competing Interests: The authors have declared that no competing interests exist. |
Databáze: | MEDLINE |
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