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

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 contro...

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Published in:Nature communications Vol. 12; no. 1; pp. 4255 - 15
Main Authors: Prakash, Rohit, Sandoval, Thomas, Morati, Florian, Zagelbaum, Jennifer A., Lim, Pei-Xin, White, Travis, Taylor, Brett, Wang, Raymond, Desclos, Emilie C. B., Sullivan, Meghan R., Rein, Hayley L., Bernstein, Kara A., Krawczyk, Przemek M., Gautier, Jean, Modesti, Mauro, Vanoli, Fabio, Jasin, Maria
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 12.07.2021
Nature Publishing Group
Nature Portfolio
Subjects:
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Animals
Bloom Syndrome - genetics
Bloom Syndrome - pathology
Bloom's syndrome
Cancer
Cell Proliferation
Deoxyribonucleic acid
DNA
DNA damage
DNA helicase
DNA repair
DNA-Binding Proteins - metabolism
Embryos
Genetics
HEK293 Cells
Heterozygosity
Homologous recombination
Homologous Recombination - genetics
Homology
Humanities and Social Sciences
Humans
Life Sciences
Loss of heterozygosity
Mammalian cells
Meiosis
Mice
Mitosis
Mouse Embryonic Stem Cells - metabolism
multidisciplinary
Multiprotein Complexes - metabolism
Mutation
Mutation - genetics
Phenotype
Proteins
Rad51 Recombinase - metabolism
Recombinase
Repair
Science
Science (multidisciplinary)
Sister Chromatid Exchange
Survival Analysis
Yeast
DNA recombination
Double-strand DNA breaks
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Human SWS1, SWSAP1, and SPIDR interact with RAD51, a critical protein for homology-directed repair. Here the authors reveal roles for the mouse SWS1–SWSAP1–SPIDR complex in inter-homolog recombination, including during meiosis, and sister chromatid exchange in BLM helicase deficient cells.
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PMCID: PMC8275761
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-24205-6