Affinage

SWSAP1

ATPase SWSAP1 · UniProt Q6NVH7

Length
229 aa
Mass
24.3 kDa
Annotated
2026-06-10
11 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SWSAP1 is a RAD51 paralog that operates as the catalytic core of the human Shu complex to control the assembly and stability of RAD51 recombinase filaments during homologous recombination (PMID:21965664, PMID:39169038). It forms a stable, mutually stabilizing heterodimer with SWS1 through the SWS1 SWIM domain, and the purified SWS1·SWSAP1 complex binds single-stranded DNA and possesses DNA-stimulated ATPase activity (PMID:21965664, PMID:25659377). Biochemically, the complex preferentially engages DNA and RAD51 filaments at exposed 5' ends, where it stabilizes filaments in an ATP-binding-dependent manner and drives conformational changes in an ATP-hydrolysis-dependent manner, while enhancing RPA diffusion on ssDNA to facilitate RAD51 loading and strand exchange (PMID:39169038, PMID:40345587). SWSAP1 additionally protects nascent RAD51 filaments by directly inhibiting the FIGNL1 anti-recombinase, which otherwise dismantles RAD51 from ssDNA (PMID:30926776). Functionally, SWSAP1 acts together with SWS1, SPIDR, and PDS5B to promote RAD51 recruitment to repair foci, replication fork restart, and sister-chromatid exchange, and it is specifically required for inter-homolog HDR while being dispensable for intra-chromosomal HDR (PMID:31665741, PMID:34253720). In meiosis the complex is needed to assemble RAD51 and DMC1 on recombination intermediates, and its loss causes infertility with reduced crossovers (PMID:30305635). A homozygous frameshift deletion in SWSAP1 establishes it as a premature ovarian insufficiency disease gene (PMID:40991243).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Established SWSAP1 as a partner of SWS1 with intrinsic biochemical activities and a role in HR, defining the founding members of the human Shu complex.

    Evidence Co-IP, in vitro reconstitution of purified complex with ssDNA-binding/ATPase assays, and siRNA knockdown with an HR reporter

    PMID:21965664

    Open questions at the time
    • Did not resolve which subunit carries the ATPase active site
    • No mechanism for how the complex acts on RAD51 filaments
  2. 2015 Medium

    Mapped the SWS1 SWIM domain as the structural determinant of SWSAP1 binding, defining the interaction interface holding the core dimer together.

    Evidence Evolutionary/sequence analysis with in vivo SWIM-residue mutagenesis and interaction assays in yeast and human cells

    PMID:25659377

    Open questions at the time
    • No structure of the interface
    • Single-lab interaction readout without orthogonal biophysical confirmation
  3. 2018 High

    Demonstrated an in vivo meiotic requirement, showing the complex promotes recombinase loading and crossover formation and placing it in a BRCA2-overlapping pathway.

    Evidence Mouse knockout with immunofluorescence of RAD51/DMC1 foci on meiotic spreads and genetic epistasis with Chk2 and Brca2

    PMID:30305635

    Open questions at the time
    • Did not define the biochemical step at which recombinase loading fails
    • Molecular basis of overlap with BRCA2 unresolved
  4. 2019 High

    Identified the mechanism by which SWSAP1 stabilizes RAD51 filaments: direct antagonism of the FIGNL1 anti-recombinase.

    Evidence In vitro ssDNA-dissociation assays with purified FIGNL1 and SWSAP1, Co-IP, and double-depletion epistasis with RAD51 foci readout

    PMID:30926776

    Open questions at the time
    • Structural basis of SWSAP1 inhibition of FIGNL1 not defined
    • Whether protection occurs at filament ends or along the filament unclear
  5. 2019 High

    Expanded the Shu complex to include SPIDR and PDS5B and tied the complex to RAD51 recruitment, fork restart, and sister-chromatid exchange.

    Evidence CRISPR/Cas9 knockout, reciprocal Co-IP, clonogenic survival to MMS/MMC, SCE and RAD51 foci assays with epistasis

    PMID:31665741

    Open questions at the time
    • Stoichiometry and architecture of the four-subunit complex unknown
    • Role of PDS5B-mediated cohesin link not dissected
  6. 2021 High

    Resolved the pathway specificity of the complex, establishing it as the first mitotic factor specifically required for inter-homolog HR but not intra-chromosomal HDR.

    Evidence CRISPR KO with HDR reporters distinguishing intra- vs inter-chromosomal repair, SCE assay, and Blm epistasis in mouse embryos

    PMID:34253720

    Open questions at the time
    • Molecular feature that restricts the complex to inter-homolog events unknown
    • Basis of the genetic interaction with BLM not mechanistically defined
  7. 2024 High

    Provided direct biophysical evidence that SWSAP1-SWS1 stabilizes RAD51 filaments, enables strand exchange, and enhances RPA diffusion to promote RAD51 loading.

    Evidence Single-molecule confocal microscopy with optical tweezers, in vitro strand exchange, purified binding assays, and CRISPR KO with PARP/APE1 inhibitor sensitivity

    PMID:39169038

    Open questions at the time
    • Did not separate ATP-binding from hydrolysis contributions
    • Effect of cancer variants on filament biophysics not quantified
  8. 2025 High

    Dissected the ATP cycle and DNA-end preference, showing 5'-end engagement with ATP-binding-dependent stabilization and hydrolysis-dependent conformational change of RAD51 filaments.

    Evidence Fluorescence polarization DNA binding, ATPase assays with Walker-motif mutagenesis, and fluorescence-based RAD51 filament interaction assays

    PMID:40345587

    Open questions at the time
    • No high-resolution structure of the complex on a RAD51 filament
    • Functional consequence of 5'-end specificity in cells not tested
  9. 2025 Medium

    Linked SWSAP1 loss-of-function to human disease, establishing it as a premature ovarian insufficiency gene.

    Evidence Exome/genome sequencing of a POI patient, IH-HR functional assay in mouse ES cells, western blot, and in silico modelling

    PMID:40991243

    Open questions at the time
    • Single patient limits genetic certainty
    • Genotype-phenotype spectrum across additional families undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the full SWS1-SWSAP1-SPIDR-PDS5B complex is architecturally organized and how it is mechanistically restricted to inter-homolog recombination remain unresolved.
  • No structure of the assembled complex on DNA or RAD51 filaments
  • Molecular basis of inter-homolog vs intra-chromosomal pathway choice unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0008092 cytoskeletal protein binding 2 GO:0016787 hydrolase activity 2 GO:0098772 molecular function regulator activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 3 R-HSA-1474165 Reproduction 2
Partners
BRCA2DMC1FIGNL1PDS5BRAD51SPIDRSWS1
Complex memberships
Shu complex (SWS1-SWSAP1-SPIDR-PDS5B)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 SWSAP1 (C19orf39) forms a stable complex with hSWS1 in vivo and in vitro; the two proteins are mutually interdependent for their stability. The purified hSWS1·SWSAP1 complex possesses single-stranded DNA-binding activity and DNA-stimulated ATPase activity. SWSAP1 also interacts with RAD51 and RAD51 paralogs, and depletion of SWSAP1 causes defects in homologous recombination repair. Co-immunoprecipitation, in vitro reconstitution of purified complex, ssDNA-binding assay, ATPase assay, siRNA knockdown with HR reporter assay The Journal of biological chemistry High 21965664
2015 The SWIM domain (CXC…Xn…CXHXXA) of SWS1 is required for protein-protein interactions with SWSAP1 in humans; in vivo disruption of invariant residues within the canonical SWIM domain inhibits these interactions. The SWS1 family is evolutionarily conserved from early-branching eukaryotes to humans. Sequence/evolutionary analysis combined with in vivo mutagenesis of SWIM domain residues and protein-interaction assays in yeast and human cells Genetics Medium 25659377
2018 The SWS1-SWSAP1 complex is required in mouse meiosis to promote assembly of RAD51 and DMC1 on early meiotic HR intermediates; loss of SWSAP1 leads to male and female infertility with reduced crossover formation. Loss of CHK2 rescues female fertility without restoring crossover numbers (crossover homeostasis). Concomitant loss of the BRCA2 C-terminus aggravates meiotic defects in Swsap1 mutant spermatocytes, placing SWS1-SWSAP1 in an overlapping pathway with BRCA2. Mouse knockout, immunofluorescence of meiotic chromosome spreads for RAD51/DMC1 foci, genetic epistasis (Swsap1/Chk2 and Swsap1/Brca2 double mutants) Nature communications High 30305635
2019 SWSAP1 protects RAD51 filaments by antagonizing FIGNL1, an AAA+ ATPase anti-recombinase. FIGNL1 binds both RAD51 and SWSAP1; purified FIGNL1 promotes dissociation of RAD51 from ssDNA via its RAD51-binding activity (independent of its ATPase). Purified SWSAP1 inhibits this RAD51-dismantling activity of FIGNL1. Depletion of FIGNL1 suppresses the defective DNA damage-induced RAD51 assembly seen in SWSAP1-deficient cells during mitosis and meiosis. In vitro ssDNA dissociation assay with purified FIGNL1, purified SWSAP1 inhibition assay, Co-IP/binding assays, siRNA/shRNA knockdown with RAD51 foci quantification, genetic epistasis (double depletion) Nature communications High 30926776
2019 SWSAP1 and SWS1 (Shu complex) function with SPIDR and PDS5B in the same genetic pathway to regulate RAD51 recruitment to DNA repair foci and replication fork restart. CRISPR/Cas9 deletion of SWSAP1 or SWS1 sensitizes cells to MMS and MMC and reduces sister-chromatid exchanges. SPIDR and PDS5B were identified as novel Shu complex interacting partners. CRISPR/Cas9 knockout, co-immunoprecipitation (SPIDR and PDS5B interaction), clonogenic survival assays, SCE assay, RAD51 foci quantification, genetic epistasis Nucleic acids research High 31665741
2021 The SWS1-SWSAP1-SPIDR complex specifically controls inter-homolog HDR and sister-chromatid exchange, but is not essential for intra-chromosomal HDR. It is the first mitotic factor identified specifically required for inter-homolog HR. Loss of SWSAP1 prolongs survival of BLM-deficient embryos, demonstrating a genetic interaction between the Shu complex and BLM helicase. CRISPR/Cas9 knockout, defined HDR reporter assays distinguishing intra- vs. inter-chromosomal repair, SCE assay, genetic epistasis with Blm mutants in mouse embryos Nature communications High 34253720
2024 Purified SWSAP1-SWS1 binds RAD51, maintains RAD51 filament stability, enables strand exchange, and decorates RAD51 filaments proficient for HR. SWSAP1-SWS1 also enhances RPA diffusion on ssDNA, providing a mechanism for promoting RAD51 loading. Cancer variants in SWSAP1 alter Shu complex formation. SWSAP1 and SWS1 knockout cells are sensitive to PARP and APE1 inhibition. Single-molecule confocal fluorescence microscopy combined with optical tweezers, in vitro strand exchange assay, purified protein binding assays, CRISPR KO with pharmacological sensitivity assays Nature communications High 39169038
2025 Purified hSWS1-SWSAP1 preferentially binds DNA with an exposed 5' end in the presence of adenine nucleotides; DNA-stimulated ATPase activity confirmed by site-specific mutagenesis with 5'-end DNA being most efficient. hSWS1-SWSAP1 initially contacts RAD51 filaments at the 5' end, induces ATP hydrolysis-dependent conformational changes in RAD51 filaments, and stabilizes filaments in an ATP binding-dependent (but hydrolysis-independent) manner. Fluorescence polarization DNA-binding assay, ATPase assay with site-specific mutagenesis of Walker motif, fluorescence-based RAD51 filament interaction assays with purified proteins The Journal of biological chemistry High 40345587
2025 A homozygous frameshift deletion in SWSAP1 (c.353del) in a patient with premature ovarian insufficiency results in absence of inter-homolog HR activity in Swsap1-/- cells and destabilization of the truncated SWSAP1 protein, establishing SWSAP1 as a POI disease gene. Exome/genome sequencing, IH-HR functional assay in mouse embryonic stem cells, western blot, in silico structural modelling Human reproduction (Oxford, England) Medium 40991243

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 RAD-ical New Insights into RAD51 Regulation. Genes 105 30551670
2011 hSWS1·SWSAP1 is an evolutionarily conserved complex required for efficient homologous recombination repair. The Journal of biological chemistry 63 21965664
2019 Human RAD51 paralogue SWSAP1 fosters RAD51 filament by regulating the anti-recombinase FIGNL1 AAA+ ATPase. Nature communications 56 30926776
2018 Shu complex SWS1-SWSAP1 promotes early steps in mouse meiotic recombination. Nature communications 45 30305635
2021 Distinct pathways of homologous recombination controlled by the SWS1-SWSAP1-SPIDR complex. Nature communications 38 34253720
2019 The human Shu complex functions with PDS5B and SPIDR to promote homologous recombination. Nucleic acids research 36 31665741
2015 Evolutionary and functional analysis of the invariant SWIM domain in the conserved Shu2/SWS1 protein family from Saccharomyces cerevisiae to Homo sapiens. Genetics 33 25659377
2024 The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA. Nature communications 9 39169038
2024 The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA. bioRxiv : the preprint server for biology 3 38405734
2025 The role of human Shu complex in ATP-dependent regulation of RAD51 filaments during homologous recombination-associated DNA damage response. The Journal of biological chemistry 1 40345587
2025 SWS1-complex in premature ovarian insufficiency: SWSAP1 as a new POI gene. Human reproduction (Oxford, England) 1 40991243

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