BRCA2-DSS1 interaction is dispensable for RAD51 recruitment at replication-induced and meiotic DNA double strand breaks

Abstract

The interaction between tumor suppressor BRCA2 and DSS1 is essential for RAD51 recruitment and repair of DNA double stand breaks (DSBs) by homologous recombination (HR). We have generated mice with a leucine to proline substitution at position 2431 of BRCA2, which disrupts this interaction. Although a significant number of mutant mice die during embryogenesis, some homozygous and hemizygous mutant mice undergo normal postnatal development. Despite lack of radiation induced RAD51 foci formation and a severe HR defect in somatic cells, mutant mice are fertile and exhibit normal RAD51 recruitment during meiosis. We hypothesize that the presence of homologous chromosomes in close proximity during early prophase I may compensate for the defect in BRCA2-DSS1 interaction. We show the restoration of RAD51 foci in mutant cells when Topoisomerase I inhibitor-induced single strand breaks are converted into DSBs during DNA replication. We also partially rescue the HR defect by tethering the donor DNA to the site of DSBs using streptavidin-fused Cas9. Our findings demonstrate that the BRCA2-DSS1 complex is dispensable for RAD51 loading when the homologous DNA is close to the DSB.

AVENGERS: Analysis of Variant Effects using Next Generation sequencing to EnhanceBRCA2Stratification

“…Notably, we identified 9 SNVs as non-functional in our dataset that were classified as (likely) pathogenic on ClinVar or by ENIGMA expert guidelines. For instance, p.Leu2510Pro (c.7529T>C) was identified in 2 cases and 1 control, and its deleterious effect was previously characterized 35,43,52 . Other SNVs from the helical domain include p.Ile2627Phe(c.7879A>T), p.Leu2647Pro(c.7940T>C), p.Leu2653Pro(c.7958T>C), p.Ile2675Val(c.8023A>G).…”

IGF‐I protects porcine granulosa cells from hypoxia‐induced apoptosis by promoting homologous recombination repair through the PI3K/AKT/E2F8/RAD51 pathway

“…A study found that BRCA2-DSS1 interaction is dispensable for RAD51 recruitment at replication-induced and meiotic DNA double-strand breaks. 50 This may indicate that BRCA2 is not necessary for IGF-1-mediated HR repair.…”

“…What is more, we noticed the result in Figure 4B showed IGF‐I failed to upregulate BRCA2 mRNA during hypoxia condition. A study found that BRCA2‐DSS1 interaction is dispensable for RAD51 recruitment at replication‐induced and meiotic DNA double‐strand breaks 50 . This may indicate that BRCA2 is not necessary for IGF‐1‐mediated HR repair.…”

Sem1/DSS1 accelerates ATP-dependent substrate unfolding by the proteasome through a conformation-dependent intercomplex contact

“…DSS1 protects the genome via its role in the BRCA2 complex; however, in apparent contrast to this role, high DSS1 expression increases cellular tolerance to DNA damage independently of BRCA2. In fact, interaction of BRCA2 with DSS1 is dispensable for DNA repair under some conditions (Mishra, et al, 2022). Similarly, breast cancers expressing high levels of DSS1 have worse prognoses and shorter recurrence-free survival times (Gondo, et al, 2021; Rezano, et al, 2013) despite frequently lacking BRCA2.…”