BRC‐1 acts in the inter‐sister pathway of meiotic double‐strand break repair

Abstract

The breast and ovarian cancer susceptibility protein BRCA1 is evolutionarily conserved and functions in DNA double-strand break (DSB) repair through homologous recombination, but its role in meiosis is poorly understood. By using genetic analysis, we investigated the role of the Caenorhabditis elegans BRCA1 orthologue (brc-1) during meiotic prophase. The null mutant in the brc-1 gene is viable, fertile and shows the wild-type complement of six bivalents in most diakinetic nuclei, which is indicative of successful crossover recombination. However, brc-1 mutants show an abnormal increase in apoptosis and RAD-51 foci at pachytene that are abolished by loss of spo-11 function, suggesting a defect in meiosis rather than during premeiotic DNA replication. In genetic backgrounds in which chiasma formation is abrogated, such as him-14/MSH4 and syp-2, loss of brc-1 leads to chromosome fragmentation suggesting that brc-1 is dispensable for crossing over but essential for DSB repair through inter-sister recombination.

Meiotic double strand breaks repair in sexually reproducing eukaryotes: We are not all equal

“…Such behaviour however is sexually dimorphic, indeed BRCA1 is not required for oocyte meiosis [28]. In C. elegans oogenesis, in line with the observation made in mice, brc-1 is dispensable for CO formation since mutations in brc-1 only mildly affect X chromosome non-disjunction and have no effects on autosomes segregation [29].…”

“…Genetic analysis suggests that the C. elegans SMC-5/6 proteins are required in meiosis for the processing of homolog-independent, presumably SCH-mediated, recombination repair [40]. Analogously, the brc-1 gene appears necessary for inter-sister homologous recombination in meiosis [29].…”

Germ Cell Apoptosis and DNA Damage Responses

“…During meiosis, HR is a more tricky undertaking. Meiotic cells must differentiate between the homologous chromosome as a template to facilitate homologous meiotic recombination, as opposed to using the sister chromatid to facilitate DNA double-strand break repair (Couteau and Zetka 2011 ;Bickel et al 2010 ;Adamo et al 2008 ) . The two related protein kinases ATM and ATR are critically important regulators of DNA damage responses in cells.…”

“…The former mode of HR is required for meiotic cross-over recombination and gene conversion. Both C. elegans brc-1, the worm homolog of the mammalian breast and ovarian cancer susceptibility gene BRCA1, and the structural maintenance of chromosomes (SMC) proteins SMC-5 and SMC-6 were shown to be speci fi cally required for meiotic sister-chromatid recombination (Bickel et al 2010 ;Adamo et al 2008 ) . In the corresponding mutants, no overt defect in meiotic cross-over recombination can be observed and chiasmata occur as in wild type.…”

“…In wildtype spo-11 -dependent RAD-51 foci are generated in the transition zone and are generally repaired in the early and mid-pachytene stages. In pairing defective mutants, foci stay, but appear to be repaired in the very late pachytene stage (independent of non-homologous end-joining), likely by sister chromatid templated repair (Adamo et al 2008 ;Colaiacovo et al 2003 ;Alpi et al 2003 ) . It is intriguing that germ cell apoptosis induction also affects these very late-stage pachytene cells.…”