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Drosophila brca2 is required for mitotic and meiotic DNA repair and efficient activation of the meiotic recombination checkpoint.

ABSTRACT: Heterozygous mutations in the tumor suppressor BRCA2 confer a high risk of breast and other cancers in humans. BRCA2 maintains genome stability in part through the regulation of Rad51-dependent homologous recombination. Much about its precise function in the DNA damage responses is, however, not yet known. We have made null mutations in the Drosophila homolog of BRCA2 and measured the levels of homologous recombination, non-homologous end-joining, and single-strand annealing in the pre-meiotic germline of Drosophila males. We show that repair by homologous recombination is dramatically decreased in Drosophila brca2 mutants. Instead, large flanking deletions are formed, and repair by the non-conservative single-strand annealing pathway predominates. We further show that during meiosis, Drosophila Brca2 has a dual role in the repair of meiotic double-stranded breaks and the efficient activation of the meiotic recombination checkpoint. The eggshell patterning defects that result from activation of the meiotic recombination checkpoint in other meiotic DNA repair mutants can be strongly suppressed by mutations in brca2. In addition, Brca2 co-immunoprecipitates with the checkpoint protein Rad9, suggesting a direct role for Brca2 in the transduction of the meiotic recombination checkpoint signal.

SUBMITTER: Klovstad M

PROVIDER: S-EPMC2233675 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Transposable elements (TEs) are endogenous mutagens and their harmful effects are especially evident in syndromes of hybrid dysgenesis. In Drosophila virilis, hybrid dysgenesis is a syndrome of incomplete gonadal atrophy that occurs when males with multiple active TE families fertilize females that lack active copies of the same families. This has been demonstrated to cause the transposition of paternally inherited TE families, with gonadal atrophy driven by the death of germline stem cells. Because there are abundant, active TEs in the male inducer genome, that are not present in the female reactive genome, the D. virilis syndrome serves as an excellent model for understanding the effects of hybridization between individuals with asymmetric TE profiles. Results:Using the D. virilis syndrome of hybrid dysgenesis as a model, we sought to determine how the landscape of germline recombination is affected by parental TE asymmetry. Using a genotyping-by-sequencing approach, we generated a high-resolution genetic map of D. virilis and show that recombination rate and TE density are negatively correlated in this species. We then contrast recombination events in the germline of dysgenic versus non-dysgenic F1 females to show that the landscape of meiotic recombination is hardly perturbed during hybrid dysgenesis. In contrast, hybrid dysgenesis in the female germline increases transmission of chromosomes with mitotic recombination. Using a de novo PacBio assembly of the D. virilis inducer genome we show that clusters of mitotic recombination events in dysgenic females are associated with genomic regions with transposons implicated in hybrid dysgenesis. Conclusions:Overall, we conclude that increased mitotic recombination is likely the result of early TE activation in dysgenic progeny, but a stable landscape of meiotic recombination indicates that either transposition is ameliorated in the adult female germline or that regulation of meiotic recombination is robust to ongoing transposition. These results indicate that the effects of parental TE asymmetry on recombination are likely sensitive to the timing of transposition.

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Drosophila brca2 is required for mitotic and meiotic DNA repair and efficient activation of the meiotic recombination checkpoint.

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