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

Arun Prakash Mishra, Suzanne A. Hartford, Sounak Sahu, Kimberly Klarmann, Rajani Kant Chittela, Kajal Biswas, Albert B. Jeon, Betty K. Martin, Sandra Burkett, Eileen Southon, Susan Reid, Mary E. Albaugh, Baktiar Karim, Lino Tessarollo, Jonathan R. Keller and Shyam K. Sharan ()
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Arun Prakash Mishra: National Cancer Institute, National Institutes of Health
Suzanne A. Hartford: National Cancer Institute, National Institutes of Health
Sounak Sahu: National Cancer Institute, National Institutes of Health
Kimberly Klarmann: National Cancer Institute, National Institutes of Health
Rajani Kant Chittela: National Cancer Institute, National Institutes of Health
Kajal Biswas: National Cancer Institute, National Institutes of Health
Albert B. Jeon: Inc. Frederick National Laboratory for Cancer Research
Betty K. Martin: National Cancer Institute, National Institutes of Health
Sandra Burkett: National Cancer Institute, National Institutes of Health
Eileen Southon: National Cancer Institute, National Institutes of Health
Susan Reid: National Cancer Institute, National Institutes of Health
Mary E. Albaugh: National Cancer Institute, National Institutes of Health
Baktiar Karim: Inc. Frederick National Laboratory for Cancer Research
Lino Tessarollo: National Cancer Institute, National Institutes of Health
Jonathan R. Keller: National Cancer Institute, National Institutes of Health
Shyam K. Sharan: National Cancer Institute, National Institutes of Health

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29409-y

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