Distinct pathways of homologous recombination controlled by the SWS1–SWSAP1–SPIDR complex

Rohit Prakash (), Thomas Sandoval, Florian Morati, Jennifer A. Zagelbaum, Pei-Xin Lim, Travis White, Brett Taylor, Raymond Wang, Emilie C. B. Desclos, Meghan R. Sullivan, Hayley L. Rein, Kara A. Bernstein, Przemek M. Krawczyk, Jean Gautier, Mauro Modesti, Fabio Vanoli and Maria Jasin ()
Additional contact information
Rohit Prakash: Memorial Sloan Kettering Cancer Center
Thomas Sandoval: Memorial Sloan Kettering Cancer Center
Florian Morati: Cancer Research Center of Marseille, CNRS, Inserm, Institut Paoli-Calmettes, Aix-Marseille Université
Jennifer A. Zagelbaum: Columbia University
Pei-Xin Lim: Memorial Sloan Kettering Cancer Center
Travis White: Memorial Sloan Kettering Cancer Center
Brett Taylor: Memorial Sloan Kettering Cancer Center
Raymond Wang: Memorial Sloan Kettering Cancer Center
Emilie C. B. Desclos: Amsterdam University Medical Centers
Meghan R. Sullivan: University of Pittsburgh School of Medicine
Hayley L. Rein: University of Pittsburgh School of Medicine
Kara A. Bernstein: University of Pittsburgh School of Medicine
Przemek M. Krawczyk: Amsterdam University Medical Centers
Jean Gautier: Columbia University
Mauro Modesti: Cancer Research Center of Marseille, CNRS, Inserm, Institut Paoli-Calmettes, Aix-Marseille Université
Fabio Vanoli: Memorial Sloan Kettering Cancer Center
Maria Jasin: Memorial Sloan Kettering Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Homology-directed repair (HDR), a critical DNA repair pathway in mammalian cells, is complex, leading to multiple outcomes with different impacts on genomic integrity. However, the factors that control these different outcomes are often not well understood. Here we show that SWS1–SWSAP1-SPIDR controls distinct types of HDR. Despite their requirement for stable assembly of RAD51 recombinase at DNA damage sites, these proteins are not essential for intra-chromosomal HDR, providing insight into why patients and mice with mutations are viable. However, SWS1–SWSAP1-SPIDR is critical for inter-homolog HDR, the first mitotic factor identified specifically for this function. Furthermore, SWS1–SWSAP1-SPIDR drives the high level of sister-chromatid exchange, promotes long-range loss of heterozygosity often involved with cancer initiation, and impels the poor growth of BLM helicase-deficient cells. The relevance of these genetic interactions is evident as SWSAP1 loss prolongs Blm-mutant embryo survival, suggesting a possible druggable target for the treatment of Bloom syndrome.

Date: 2021
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DOI: 10.1038/s41467-021-24205-6

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