| RRC ID |
59371
|
| Author |
Li Q, Saito TT, Martinez-Garcia M, Deshong AJ, Nadarajan S, Lawrence KS, Checchi PM, Colaiacovo MP, Engebrecht J.
|
| Title |
The tumor suppressor BRCA1-BARD1 complex localizes to the synaptonemal complex and regulates recombination under meiotic dysfunction in Caenorhabditis elegans.
|
| Journal |
PLoS Genet
|
| Abstract |
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.
|
| Volume |
14(11)
|
| Pages |
e1007701
|
| Published |
2018-11-1
|
| DOI |
10.1371/journal.pgen.1007701
|
| PII |
PGENETICS-D-18-00486
|
| PMID |
30383767
|
| PMC |
PMC6211623
|
| MeSH |
Alleles
Animals
BRCA1 Protein / genetics
BRCA1 Protein / metabolism*
Caenorhabditis elegans / genetics*
Caenorhabditis elegans / metabolism*
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism
DNA Replication
Embryo, Nonmammalian
Genes, Reporter
Germ Cells
Meiosis / genetics*
Protein Transport
Rad51 Recombinase / genetics
Rad51 Recombinase / metabolism
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Recombination, Genetic*
Synaptonemal Complex / metabolism*
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
|
| IF |
5.224
|
| Times Cited |
5
|
| Resource |
| C.elegans |
tm1145
tm1813 |
