Affinage

SPIDR

DNA repair-scaffolding protein · UniProt Q14159

Length
915 aa
Mass
100.3 kDa
Annotated
2026-06-10
12 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPIDR (scaffolding protein involved in DNA repair) is a scaffold that coordinates homologous recombination by physically and independently bridging BLM helicase and the RAD51 recombinase, promoting assembly of a BLM/RAD51-containing complex; its depletion elevates sister chromatid exchange and impairs HR (PMID:23509288). SPIDR operates as part of the SWS1–SWSAP1–SPIDR complex (the human Shu complex), additionally engaging PDS5B, and this complex is required for stable RAD51 loading at damage sites, controls distinct homology-directed repair outcomes including inter-homolog HDR, regulates replication fork restart after stalling, and underlies the poor growth of BLM-deficient cells (PMID:34253720, PMID:31665741). During meiosis SPIDR governs assembly or stability of RAD51/DMC1 nucleoprotein filaments on ssDNA, and its loss in male mice causes complete meiotic arrest with synapsis and crossover defects, while female subfertility is partially rescued by ablation of the checkpoint kinase CHK2 (PMID:36938872). Biallelic loss-of-function mutations in humans impair HR and produce chromosomal instability, with one nonsense variant leaving sister chromatid exchange normal, indicating SPIDR acts in vivo chiefly through the RAD51 rather than the BLM arm (PMID:27967308, PMID:34697795). SPIDR transcription is activated by NRF1 binding a super enhancer, placing SPIDR downstream of NRF1 in the oxidative stress response (PMID:38438958).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2013 High

    Established that a single protein could physically couple BLM helicase to RAD51, answering how these recombination factors are co-assembled into one DNA-processing complex.

    Evidence Reciprocal Co-IP, siRNA depletion with SCE and HR reporter assays, damage sensitivity and foci analysis in human cells

    PMID:23509288

    Open questions at the time
    • Did not define which domains of SPIDR bind BLM versus RAD51
    • No in vivo or organismal phenotype established
  2. 2017 Medium

    Demonstrated SPIDR is required for HR in humans, connecting the molecular scaffold to a disease-relevant DNA repair defect.

    Evidence Whole-exome sequencing of a biallelic stop-gain variant plus EGFP DSB repair assay and 53BP1/γH2AX immunofluorescence in patient cells

    PMID:27967308

    Open questions at the time
    • Single lab, patient cells only
    • Did not separate BLM-dependent from RAD51-dependent contributions
  3. 2019 High

    Placed SPIDR within a defined SWS1–SWSAP1 (Shu) complex with PDS5B, clarifying the protein assembly through which it promotes RAD51 recruitment and fork restart.

    Evidence Co-IP, CRISPR deletion of SWS1/SWSAP1, RAD51 foci, SCE, and MMS/MMC sensitivity with epistasis

    PMID:31665741

    Open questions at the time
    • Stoichiometry and architecture of the complex not resolved
    • Mechanism of PDS5B linkage to RAD51 loading unclear
  4. 2021 High

    Resolved the pathway-specific function of the complex, identifying it as the first mitotic factor specific to inter-homolog HDR and genetically epistatic to BLM.

    Evidence CRISPR KO, mouse genetic epistasis with Blm, pathway-specific HDR reporters, RAD51 foci and SCE assays

    PMID:34253720

    Open questions at the time
    • Biochemical mechanism distinguishing inter-homolog from inter-sister repair not defined
  5. 2021 Medium

    Showed that a human SPIDR null variant produces chromosomal instability with normal SCE, dissecting SPIDR's primary in vivo role toward RAD51 rather than BLM.

    Evidence Targeted NGS, mitomycin C breakage and metaphase analysis, and SCE assay in patient cells

    PMID:34697795

    Open questions at the time
    • Single patient/lab
    • Discordance with cell-line SCE phenotypes not mechanistically reconciled
  6. 2023 High

    Extended SPIDR function to meiosis, showing it controls RAD51/DMC1 filament assembly required for synapsis and crossover formation in vivo.

    Evidence Conditional KO mouse, meiotic spreads, RAD51/DMC1 foci, synapsis analysis, CHK2 epistasis

    PMID:36938872

    Open questions at the time
    • Why CHK2 ablation rescues females but not males is unexplained
    • Direct biochemical effect on filament nucleation versus stabilization not separated
  7. 2024 Medium

    Identified upstream transcriptional control, showing NRF1 drives SPIDR expression via a super enhancer to support an oxidative stress response.

    Evidence ChIP-qPCR for NRF1/H3K27ac, siRNA knockdown, overexpression rescue, ROS/MDA/SOD/γH2AX assays with JQ1 in HCC cells

    PMID:38438958

    Open questions at the time
    • Single lab/cell-type context
    • How HR scaffolding relates mechanistically to ROS handling not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of how SPIDR simultaneously engages BLM, RAD51/DMC1, and the SWS1–SWSAP1–PDS5B complex, and how it biases repair toward inter-homolog HDR, remains unresolved.
  • No structural model of SPIDR or its complexes
  • Domain-level mapping of partner-binding interfaces absent
  • Mechanism coupling transcriptional control to repair output unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-73894 DNA Repair 5 R-HSA-1474165 Reproduction 1
Partners
BLMDMC1PDS5BRAD51SWS1SWSAP1
Complex memberships
BLM/RAD51-containing complexSWS1-SWSAP1-SPIDR (Shu) complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 SPIDR (scaffolding protein involved in DNA repair) independently interacts with both BLM helicase and RAD51, and promotes the formation of a BLM/RAD51-containing complex. Depletion of SPIDR increases sister chromatid exchange rates and causes defects in homologous recombination, establishing SPIDR as a scaffold linking BLM and RAD51 in a multifunctional DNA-processing complex. Co-immunoprecipitation, siRNA depletion with sister chromatid exchange assay, HR reporter assay, DNA damage sensitivity assays, immunofluorescence foci analysis Proceedings of the National Academy of Sciences of the United States of America High 23509288
2021 SPIDR functions as part of the SWS1-SWSAP1-SPIDR complex to control distinct types of homology-directed repair (HDR). This complex is required for stable RAD51 assembly at DNA damage sites, is critical for inter-homolog HDR (the first mitotic factor identified specifically for this function), drives high-level sister chromatid exchange, promotes long-range loss of heterozygosity, and is required for the poor growth phenotype of BLM-deficient cells. Genetic epistasis shows SWSAP1 loss prolongs Blm-mutant embryo survival. CRISPR/Cas9 knockout, genetic epistasis in mouse models, HDR pathway-specific reporter assays, RAD51 foci analysis, sister chromatid exchange assay Nature communications High 34253720
2019 SPIDR interacts with SWS1 and SWSAP1 (the human Shu complex) and also with PDS5B, forming a complex that functions in the same genetic pathway upon DNA damage. This complex promotes RAD51 recruitment to DNA repair foci, regulates replication fork restart after stalling, and is required for normal sister chromatid exchange levels. Co-immunoprecipitation, CRISPR/Cas9 deletion of SWS1 and SWSAP1, RAD51 foci analysis, sister chromatid exchange assay, DNA damage sensitivity assay (MMS, MMC) Nucleic acids research High 31665741
2023 SPIDR regulates the assembly or stability of RAD51/DMC1 nucleoprotein filaments on ssDNA during meiosis. Knockout of Spidr in male mice causes complete meiotic arrest with defects in synapsis and crossover formation, leading to male infertility. In females, Spidr loss causes subfertility, and this is partially rescued by ablation of the DNA damage checkpoint kinase CHK2 in females but not males. Conditional knockout mouse model, meiotic spread analysis, RAD51/DMC1 foci immunofluorescence, synapsis analysis, genetic epistasis with CHK2 knockout Nucleic acids research High 36938872
2017 A biallelic stop-gain mutation in SPIDR (c.839G>A, p.W280*) alters homologous recombination activity in human patient cells, resulting in accumulation of 53BP1-labeled DSBs post-ionizing radiation and γH2AX-labeled damage during unperturbed growth, establishing SPIDR as required for HR in vivo in humans. Whole-exome sequencing, EGFP-based DSB repair pathway assay, 53BP1 and γH2AX immunofluorescence in patient blood-derived cells The Journal of clinical endocrinology and metabolism Medium 27967308
2021 A homozygous nonsense variant in SPIDR (c.814C>T, R272*) in a human patient causes chromosomal instability manifesting as increased mitomycin C-induced DNA breaks and aberrant metaphases, consistent with impairment of the RAD51 pathway. Notably, sister chromatid exchanges were normal (unlike BLM pathway defects), indicating SPIDR's primary in vivo role is through RAD51 rather than BLM. Targeted next-generation sequencing, mitomycin C-induced chromosome breakage assay, metaphase analysis, sister chromatid exchange assay in patient cells Clinical genetics Medium 34697795
2024 NRF1 transcription factor activates SPIDR transcription by binding to a super enhancer (SE) region of SPIDR (confirmed by ChIP-qPCR). SPIDR depletion in HCC cells increases reactive oxygen species, malondialdehyde, and γH2AX levels, and decreases SOD levels and cell proliferation under oxidative stress; overexpression of SPIDR partially rescues effects of NRF1 silencing, placing SPIDR downstream of NRF1 in oxidative stress response. ChIP-qPCR for NRF1 binding and H3K27ac at SPIDR SE, siRNA knockdown, SPIDR overexpression rescue, ROS/MDA/SOD/γH2AX assays, JQ1 BET inhibitor treatment BMC gastroenterology Medium 38438958

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Scaffolding protein SPIDR/KIAA0146 connects the Bloom syndrome helicase with homologous recombination repair. Proceedings of the National Academy of Sciences of the United States of America 61 23509288
2017 A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis. The Journal of clinical endocrinology and metabolism 45 27967308
2021 Distinct pathways of homologous recombination controlled by the SWS1-SWSAP1-SPIDR complex. Nature communications 38 34253720
2019 Circ-Spidr enhances axon regeneration after peripheral nerve injury. Cell death & disease 36 31624232
2019 The human Shu complex functions with PDS5B and SPIDR to promote homologous recombination. Nucleic acids research 36 31665741
2025 SPIDR enables multiplexed mapping of RNA-protein interactions and uncovers a mechanism for selective translational suppression upon cell stress. Cell 17 40701149
2023 SPIDR is required for homologous recombination during mammalian meiosis. Nucleic acids research 13 36938872
2021 A SPIDR homozygous nonsense pathogenic variant in isolated primary ovarian insufficiency with chromosomal instability. Clinical genetics 12 34697795
2023 SPIDR: a highly multiplexed method for mapping RNA-protein interactions uncovers a potential mechanism for selective translational suppression upon cellular stress. bioRxiv : the preprint server for biology 10 37333139
2013 Instability at the FRA8I common fragile site disrupts the genomic integrity of the KIAA0146, CEBPD and PRKDC genes in colorectal cancer. Cancer letters 10 23603433
2018 SPIDR: small-molecule peptide-influenced drug repurposing. BMC bioinformatics 9 29661129
2024 Nuclear respiratory factor 1 regulates super enhancer-controlled SPIDR to protect hepatocellular carcinoma cells from oxidative stress. BMC gastroenterology 2 38438958

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