TY - JOUR
T1 - Distinct pathways of homologous recombination controlled by the SWS1–SWSAP1–SPIDR complex
AU - Prakash, Rohit
AU - Sandoval, Thomas
AU - Morati, Florian
AU - Zagelbaum, Jennifer A.
AU - Lim, Pei-Xin
AU - White, Travis
AU - Taylor, Brett
AU - Wang, Raymond
AU - Desclos, Emilie C. B.
AU - Sullivan, Meghan R.
AU - Rein, Hayley L.
AU - Bernstein, Kara A.
AU - Krawczyk, Przemek M.
AU - Gautier, Jean
AU - Modesti, Mauro
AU - Vanoli, Fabio
AU - Jasin, Maria
N1 - Funding Information: We thank members of the Jasin laboratory for helpful discussions, especially Tai-Yuan Yu, Agnieszka Lukaszewicz, and Yufuko Akamatsu, as well as Katia Manova and members of the MSK Molecular Cytology core facility for technical help, Agnel Sfeir for the Hsp90 targeting plasmids, and Peter Romanienko for generating Spidr knockout mice. Core facilities at MSK are supported by a Cancer Center Support Grant (NIH P30 CA008748). The research was supported by NIH F32 GM110978 (R.P.), a Paoli-Calmettes Institute Ph.D. fellowship (F.M.), NIH F31 ES027321 (M.R.S.), NIH R01 ES030335 and ACS Research Scholar Grant 129182-RSG-16-043-01-DMC (K.A.B.), the French National League against Cancer (M.M.), and the MSK Functional Genomics Initiative, Cycle for Survival, NIH R35 GM118175, R01 CA185660, and R35 CA253174 (M.J.). Publisher Copyright: © 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85110645062&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-021-24205-6
DO - https://doi.org/10.1038/s41467-021-24205-6
M3 - Article
C2 - 34253720
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4255
ER -