Affinage

SMARCAL1

SNF2 related chromatin remodeling annealing helicase 1 · UniProt Q9NZC9

Length
954 aa
Mass
105.9 kDa
Annotated
2026-06-10
89 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMARCAL1 is an SNF2-family DNA translocase that maintains genome stability at stalled replication forks, where it uses ssDNA-dependent ATP hydrolysis to catalyze fork regression, branch migration, and annealing of RPA-coated single-stranded DNA (PMID:10857751, PMID:22279047, PMID:35801922). Its catalytic core combines a RecA-like ATPase module with a tandem HARP (2HP) domain that dictates the annealing helicase activity and is required for substrate binding and activation; SIOD-associated mutations in these domains abolish ATPase and remodeling activity (PMID:21525954, PMID:22279047, PMID:26195148). SMARCAL1 is targeted to damage sites through an N-terminal RPA-binding motif that engages the winged-helix domain of RPA32 (RPA32C) via a disorder-to-helix transition, while the orientation of RPA's high-affinity DBD-A/B domains at the fork junction directs its substrate specificity (PMID:19793861, PMID:24730652, PMID:24910198, PMID:25552480). Its remodeling activity is tightly regulated: ATR phosphorylation at S652 limits excessive fork regression and prevents collapse into MUS81/SLX4/CtIP-processed substrates, S889 phosphorylation relieves C-terminal autoinhibition to stimulate activity, and RFWD3-mediated ubiquitylation disengages it from RPA without degradation to protect forks from over-processing (PMID:23873943, PMID:24150942, PMID:38502677). Improperly regulated SMARCAL1 fork reversal generates substrates for nucleolytic degradation; in BRCA2-deficient cells it converts gapped forks into reversed forks subject to Mre11-dependent nascent-strand degradation, and RAD51 and the BCDX2 paralog complex stimulate its motor activity (PMID:28757209, PMID:35801922). Beyond fork remodeling, SMARCAL1 promotes NHEJ by maintaining duplex DNA ends to enable Ku/DNA-PKcs/XRCC4 recruitment, resolves replication stress at telomeres including ALT telomeres independently of RPA, and partners with BRG1 to co-regulate transcription of c-Myc, ATM, ATR, and miRNA-biogenesis genes (PMID:26578802, PMID:26089390, PMID:26648259, PMID:30317028, PMID:28716689, PMID:35784471). SMARCAL1 also limits endogenous DNA damage to suppress cGAS-STING innate immune signaling and cooperates with JUN to sustain PD-L1 expression, so that its loss enhances anti-tumor immunity (PMID:38301646). Loss-of-function mutations in SMARCAL1 cause Schimke immuno-osseous dysplasia, with disease severity inversely correlated with residual SMARCAL1 activity (PMID:11799392, PMID:18805831).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 Medium

    Establishing that SMARCAL1 is an enzyme answered whether the protein has intrinsic catalytic activity, defining it as an SNF2-family ATPase.

    Evidence In vitro ATPase assay with purified recombinant HARP/SMARCAL1

    PMID:10857751

    Open questions at the time
    • Did not identify the physiological DNA substrate
    • No link to a cellular pathway yet
  2. 2002 High

    Linking SMARCAL1 mutations to Schimke immuno-osseous dysplasia established the gene's physiological importance and a genotype-phenotype gradient before its biochemical role was known.

    Evidence Positional cloning and mutation analysis across 26 SIOD families

    PMID:11799392

    Open questions at the time
    • Did not establish the molecular function disrupted by mutation
    • Mechanism connecting loss of function to multi-system disease unresolved
  3. 2009 High

    Multiple concurrent studies answered how SMARCAL1 reaches sites of replication stress, showing direct RPA binding via an RPA-binding motif recruits it to stalled forks and that its loss causes fork breakdown.

    Evidence RBM characterization, reciprocal Co-IP, immunofluorescence, in vitro helicase assays, siRNA with RAD51/cell-cycle readouts, Xenopus extracts, patient fibroblast reconstitution

    PMID:19793861 PMID:19793862 PMID:19841479

    Open questions at the time
    • Catalytic reaction at the fork not yet defined
    • Domain basis of activity not mapped
  4. 2011 High

    Defining the HARP (2HP) domain as the determinant of annealing helicase activity answered which module couples ATP hydrolysis to remodeling, shown by transferable function in SNF2-domain chimeras.

    Evidence Domain deletion/chimeric proteins with in vitro annealing assays and cellular complementation

    PMID:21525954

    Open questions at the time
    • Did not resolve full-length enzyme structure
    • Regulation of the catalytic domain unaddressed
  5. 2012 High

    Demonstrating SMARCAL1 catalyzes fork regression and branch migration on model forks and junctions answered what reaction it performs at forks, and its loss generates MUS81-dependent DSBs.

    Evidence DNA fiber assay, in vitro fork regression/branch migration, SAXS, homology modeling, mutagenesis, MUS81 epistasis

    PMID:22279047

    Open questions at the time
    • How activity is restrained to prevent over-processing not yet known
    • High-resolution structure of motor on substrate absent
  6. 2013 High

    Identifying ATR phosphorylation at S652 and autoinhibitory S889 phosphorylation answered how fork remodeling is balanced, defining brakes and accelerators that prevent aberrant fork collapse.

    Evidence Phospho-site mutagenesis (S652A/D, S889D), DNA fiber assays, in vitro ATPase/fork regression, mammalian and Xenopus systems

    PMID:23873943 PMID:24150942

    Open questions at the time
    • The kinase responsible for S889 not defined
    • Integration of opposing phospho-signals not resolved
  7. 2013 High

    Mapping SMARCAL1 into RPA/DNA-PKcs/WRN complexes answered how it operates relative to other fork-protective factors, showing it acts independently of and more efficiently than WRN at fork regression.

    Evidence Proteomics, reciprocal Co-IP, co-localization, in vitro fork regression, MUS81 epistasis

    PMID:23671665

    Open questions at the time
    • Functional reason for assembling these factors on shared scaffold unclear
    • DNA-PKcs role at forks not dissected
  8. 2014 High

    Structural and biophysical characterization of the SMARCAL1 RBM–RPA32C interface answered the atomic basis of recruitment, showing a peptide adopting an induced helix bound 1:1 to RPA32C, and that RPA DBD-A/B orientation directs substrate specificity.

    Evidence X-ray crystallography (1.4 Å; PDB 4MQV), NMR, ITC, CD, RPA domain mutant fork-regression assays

    PMID:24730652 PMID:24910198 PMID:25552480

    Open questions at the time
    • Structure of full SMARCAL1 engaging an RPA-coated fork absent
    • Allosteric link from RPA contact to motor activation incomplete
  9. 2015 High

    Defining telomere, NHEJ, and transcriptional functions broadened SMARCAL1's role beyond canonical fork reversal, with an RPA-independent telomere activity unique among SNF2 paralogs.

    Evidence Telomere FISH and C-circle assays, RPA-binding mutants, paralog comparison, DT40/TK6 gene disruption with NHEJ epistasis, ChIP at c-myc promoter

    PMID:26089390 PMID:26578802 PMID:26648259

    Open questions at the time
    • The RPA-independent telomere recruitment mechanism unknown
    • How a fork-remodeler also acts as a transcriptional co-regulator unresolved
  10. 2017 High

    Showing SMARCAL1-mediated fork reversal feeds Mre11-dependent nascent-strand degradation in BRCA2-deficient cells answered why its activity can be deleterious, framing it as a double-edged remodeler controlled by RAD51 filament stability.

    Evidence Xenopus extracts with Brca2/Smarcal1 depletion, DNA fiber assays, EM of fork structures, Mre11 inhibition and Rad51 mutant epistasis

    PMID:28757209

    Open questions at the time
    • Threshold distinguishing protective vs degradative reversal not defined
    • In vivo relevance to BRCA-mutant tumors not tested here
  11. 2022 High

    Reconstitution distinguishing ATP-independent annealing from ATP-driven re-zipping, plus RAD51/BCDX2 stimulation, answered the precise biochemical repertoire and how it is positively regulated by recombination factors.

    Evidence Purified-protein DNA annealing, ATPase translocase, branch migration assays, physical-interaction pulldowns

    PMID:35801922

    Open questions at the time
    • Stoichiometry and structural basis of RAD51/BCDX2 stimulation undefined
    • Coordination of the two activities at a single fork unclear
  12. 2024 High

    Identifying RFWD3 ubiquitylation as a non-degradative switch that disengages SMARCAL1 from RPA answered an additional layer of restraint protecting forks from excessive MUS81 cleavage.

    Evidence In vitro ubiquitylation reconstitution, Co-IP, ubiquitylation-defective mutants, MUS81 epistasis, DNA fiber assays

    PMID:38502677

    Open questions at the time
    • Ubiquitylated residues and reversal of the modification not detailed
    • Interplay with phospho-regulation unresolved
  13. 2024 High

    Connecting SMARCAL1 to cGAS-STING suppression and PD-L1 maintenance answered how a genome-stability factor shapes tumor immunity, defining it as a target whose loss sensitizes tumors to checkpoint blockade.

    Evidence SMARCAL1 KO in cancer cells, cGAS-STING reporters, ATAC-seq, JUN ChIP, mouse melanoma model with immune checkpoint blockade

    PMID:38301646

    Open questions at the time
    • Whether fork-remodeling activity per se drives the immune phenotype not separated from chromatin role
    • Mechanism of JUN cooperation at PD-L1 element not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SMARCAL1's biochemically distinct activities — fork reversal, NHEJ end protection, telomere maintenance, transcriptional co-regulation, lipid-gene control, and immune modulation — are partitioned and coordinated within a cell remains unresolved.
  • No unifying model integrating nuclear genome-stability roles with cytoplasmic/peroxisomal and transcriptional functions
  • Structure of full-length enzyme on physiological substrates lacking
  • Determinants selecting between competing regulators (ATR, RFWD3, CSB, RAD51/BCDX2) at a given fork undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0140657 ATP-dependent activity 4 GO:0140097 catalytic activity, acting on DNA 3 GO:0003677 DNA binding 2 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 2 GO:0005777 peroxisome 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-69306 DNA Replication 3 R-HSA-73894 DNA Repair 3 R-HSA-168256 Immune System 1
Partners
ANGPTL3BRG1DNA-PKCSJUNRAD51RFWD3RPA32WRN

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Purified His-tagged HARP/SMARCAL1 protein exhibits single-stranded DNA-dependent ATPase activity, establishing it as a functional SNF2-family ATPase. In vitro ATPase assay with purified recombinant protein Genomics Medium 10857751
2002 Mutations in SMARCAL1 cause Schimke immuno-osseous dysplasia (SIOD); loss-of-function (nonsense/frameshift/splice) mutations cause severe disease, while missense mutations allow partial function and cause milder disease, establishing a genotype-phenotype correlation. Positional cloning, mutation analysis in 26 unrelated SIOD families Nature genetics High 11799392
2008 SIOD-associated SMARCAL1 missense mutations impair protein stability, subcellular localization, chromatin binding, and ATPase enzymatic activity; SMARCAL1 binds chromatin in vivo, and disease severity is inversely proportional to overall SMARCAL1 activity as demonstrated in Drosophila. ATPase assay, chromatin fractionation, subcellular localization studies, Drosophila expression system Journal of medical genetics Medium 18805831
2009 SMARCAL1 contains an RPA-binding motif (RBM) similar to TIPIN that is necessary and sufficient to target SMARCAL1 to stalled replication forks; RPA binding is critical for cellular function but not required for annealing helicase activity in vitro; ATM, ATR, and DNA-PK phosphorylate SMARCAL1 in response to replication stress. RPA binding motif characterization, cellular localization assays, in vitro helicase assay, kinase phosphorylation assays, siRNA knockdown with S-phase DNA damage readout Genes & development High 19793861
2009 SMARCAL1 directly interacts with RPA and is recruited to sites of DNA damage in an RPA-dependent manner; SMARCAL1-depleted cells show slower fork recovery and delayed mitotic entry after S-phase arrest; SIOD patient fibroblasts reconstituted with SMARCAL1 show faster cell cycle progression after S-phase arrest. Co-immunoprecipitation, immunofluorescence at damage foci, cell cycle analysis, patient fibroblast reconstitution Genes & development High 19793862
2009 In Xenopus egg extracts and human cells, SMARCAL1 is recruited to double-strand breaks and stalled replication forks, co-localizing with RPA; SMARCAL1 interacts physically with RPA independently of DNA; depletion of SMARCAL1 from U2OS cells leads to increased RAD51 foci upon fork stalling, indicating increased fork breakdown. Xenopus egg extract system with mass spectrometry, Co-IP, immunofluorescence, siRNA knockdown with RAD51 foci readout The Journal of biological chemistry High 19841479
2011 The conserved tandem HARP (2HP) domain dictates SMARCAL1's ATP-dependent annealing helicase activity; chimeric proteins fusing the 2HP domain of SMARCAL1 with the SNF2 domain of BRG1 or HELLS display annealing helicase activity in vitro and mimic SMARCAL1 function at replication forks in vivo. Domain deletion/chimeric protein assays, in vitro annealing helicase assay, cellular functional complementation EMBO reports High 21525954
2012 SMARCAL1 travels with elongating replication forks and catalyzes fork regression and Holliday junction branch migration; its HARP2 domain is required for substrate binding and activation; SMARCAL1 can bind and remodel three-way and four-way junctions and model replication forks; its absence leads to MUS81-dependent DSB formation; SIOD-associated mutations abrogate these activities. DNA fiber assay, in vitro fork regression/branch migration assays, SAXS, limited proteolysis, homology modeling, mutagenesis, epistasis with MUS81 Genes & development High 22279047
2013 ATR phosphorylates SMARCAL1 on S652, thereby limiting its fork regression activities and preventing aberrant fork processing/collapse when ATR is inactivated; unregulated SMARCAL1 contributes to fork collapse via generating substrates for SLX4-dependent cleavage and CtIP-dependent resection. ATR inhibitor treatment, phospho-site mutagenesis (S652A/D), DNA fiber assay, Xenopus and mammalian cell systems, epistasis analysis Genes & development High 23873943
2013 SMARCAL1 forms protein complexes with RPA, DNA-PKcs, and WRN helicase; the SMARCAL1–WRN interaction is indirect and mediated by RPA as scaffold; SMARCAL1 and WRN co-localize at stalled forks independently of each other and act independently to prevent MUS81 cleavage; SMARCAL1 catalyzes fork regression more efficiently than WRN. Proteomics/mass spectrometry, Co-IP, co-localization by immunofluorescence, in vitro fork regression assay, epistasis with MUS81 PloS one High 23671665
2013 SMARCAL1 is phosphorylated at S889 even in undamaged cells; S889 phosphorylation increases DNA-stimulated ATPase activity and fork regression activity; a phosphomimetic S889D mutant is hyperactive in cells; deletion of the C-terminal region creates a hyperactive enzyme, indicating S889 phosphorylation relieves C-terminal auto-inhibition. Mass spectrometry phospho-site identification, site-directed mutagenesis, in vitro ATPase and fork regression assays, cellular overexpression of phospho-mutants Nucleic acids research High 24150942
2014 The N-terminal RPA-binding motif (RBM) of SMARCAL1 binds the C-terminal winged-helix domain of RPA32 (RPA32C) with Kd of 2.5 μM; RPA32C binding induces a disorder-to-helix transition in the SMARCAL1 RBM; crystal structure of RPA32C was solved at 1.4 Å and the SMARCAL1 binding interface was mapped by NMR chemical shift perturbations. Isothermal titration calorimetry, circular dichroism, X-ray crystallography (1.4 Å), NMR chemical shift mapping Biochemistry High 24730652
2014 Crystal structure of RPA32C in complex with a 26-amino-acid SMARCAL1 N-terminal peptide shows 1:1 stoichiometry; SMARCAL1N adopts a long α-helical conformation; extensive mutagenesis confirmed the interaction interface; the α1/α2 loop of RPA32C undergoes conformational rearrangement upon SMARCAL1 binding. X-ray crystallography (PDB: 4MQV), ITC, NMR, mutagenesis, molecular sieving The FEBS journal High 24910198
2014 RPA high-affinity DNA-binding domains A and B (DBD-A/B) near the fork junction direct SMARCAL1 fork-remodeling activity; interaction between SMARCAL1 and RPA is essential for SMARCAL1 activation; the location of the interacting surface on RPA is not critical, but the orientation of DBD-A/B at forks determines SMARCAL1 substrate specificity; RPA DBD-C and DBD-D are not required for SMARCAL1 regulation. RPA domain mutant analysis, in vitro fork regression assay with RPA variants, cellular localization assays The Journal of biological chemistry High 25552480
2015 SMARCAL1 has an important function at telomeres; SMARCAL1-deficient cells accumulate telomere-associated DNA damage and elevated extrachromosomal C-circles; this telomere function does not require RPA interaction and is not shared by ZRANB3 or HLTF, defining a unique activity. siRNA/shRNA knockdown, telomere FISH, C-circle assay, RPA-binding mutant analysis, comparison with ZRANB3/HLTF KD Proceedings of the National Academy of Sciences of the United States of America High 26578802
2015 SMARCAL1 negatively regulates c-Myc transcription by binding to the c-myc promoter together with BRG1 and RNAPII, and using ATP hydrolysis to alter the conformation of the promoter DNA; ADAAD (bovine SMARCAL1 homolog) hydrolyzes ATP using a specific upstream region of the c-myc promoter as effector. ChIP, in vitro ATP hydrolysis assay with promoter DNA, chromatin conformation analysis, serum starvation model Scientific reports Medium 26648259
2015 SMARCAL1 promotes NHEJ-mediated DSB repair; both ATPase domain inactivation and deletion of the RPA-binding site phenocopy SMARCAL1 null in NHEJ repair; SMARCAL1 loss reduces accumulation of Ku70/DNA-PKcs and XRCC4 at DNA damage sites, suggesting SMARCAL1 maintains duplex status at DSB ends to enable NHEJ factor recruitment. Gene disruption in DT40 and TK6 cells, radiosensitivity assays, epistasis with NHEJ mutants, immunofluorescence of NHEJ factors at damage sites, domain mutant analysis Nucleic acids research High 26089390
2016 SMARCAL1 associates with ALT telomeres to resolve replication stress; in the absence of SMARCAL1, persistently stalled forks at ALT telomeres deteriorate into DSBs and promote chromosome fusions. SMARCAL1 depletion in ALT cancer cells, telomere ChIP/FISH, chromosome fusion assay, DNA damage marker co-localization Cell reports Medium 26832416
2016 BRG1 and SMARCAL1 mutually co-regulate each other's transcription: BRG1 binds the SMARCAL1 promoter and SMARCAL1 binds the BRG1 promoter; on DNA damage, occupancy of SMARCAL1 on the BRG1 promoter increases coinciding with increased BRG1 on the SMARCAL1 promoter. ChIP, qRT-PCR, siRNA knockdown Scientific reports Medium 26843359
2017 SMARCAL1-mediated fork reversal triggers Mre11-dependent degradation of nascent DNA in the absence of BRCA2/stable Rad51 nucleofilaments; BRCA2 prevents ssDNA gap accumulation at fork junctions; without BRCA2, Smarcal1 converts gapped forks into reversed forks subject to Mre11-dependent degradation; stable Rad51 nucleofilaments directly prevent Mre11-dependent DNA degradation. Xenopus laevis system, Brca2 depletion, Smarcal1 depletion, DNA fiber assay, EM of fork structures, Mre11 inhibition epistasis, Rad51 mutant analysis Molecular cell High 28757209
2017 BRG1 and SMARCAL1 co-regulate the transcription of ATM and ATR; co-occupancy of SMARCAL1 and BRG1 on ATM/ATR promoters is required for their upregulation after doxorubicin-induced DNA damage; downregulation of either protein leads to G2/M checkpoint override and mitotic abnormalities; phospho-ATM binds promoters of SMARCAL1, BRG1, ATM and ATR in a feedback loop. ChIP, siRNA knockdown, cell cycle analysis, immunofluorescence of mitotic markers Biochimica et biophysica acta. Gene regulatory mechanisms Medium 30317028
2017 BRG1 and SMARCAL1 co-regulate transcription of DROSHA, DGCR8, and DICER in response to doxorubicin-induced DSBs; this co-regulation is required for non-coding RNA production and 53BP1 foci formation; absence of SMARCAL1 specifically downregulates DROSHA, while absence of BRG1 downregulates DGCR8 and DICER. ChIP, siRNA knockdown, 53BP1 foci immunofluorescence, ncRNA rescue experiment Biochimica et biophysica acta. Gene regulatory mechanisms Medium 28716689
2019 Adenovirus E1B-55K targets SMARCAL1 for proteasomal degradation via an E1B-55K/E4orf6 cullin RING ligase complex; SMARCAL1 is phosphorylated at S123, S129, and S173 early during adenovirus infection in an ATR- and CDK-dependent manner, which contributes to its recruitment to viral replication centers; SMARCAL1 recruitment to viral centers requires RPA association. Proteasome inhibitor experiments, E1B-55K/E4orf6 co-expression, ATR and CDK pharmacological inhibition, Co-IP with E1B-55K, phospho-site mapping by mass spectrometry Journal of virology Medium 30996091
2020 CSB competes with SMARCAL1 for RPA32 at stalled forks; loss of CSB coupled with SMARCAL1 depletion synergistically promotes telomeric MUS81 recruitment and fragile telomere formation in ALT cells; CSB-mediated HR repair and SMARCAL1-mediated fork regression cooperate to prevent stalled forks from being processed into fragile telomeres. siRNA depletion, immunofluorescence, telomere FISH, RPA32C binding competition assay, epistasis analysis Journal of cell science Medium 31974116
2022 SMARCAL1 uniquely anneals RPA-coated ssDNA via direct RPA interaction in an ATP-independent manner; SMARCAL1 (with ZRANB3, but not HLTF) efficiently uses ATPase-driven translocase activity to rezip RPA-covered bubbled DNA mimicking fork reversal; RAD51 and the BCDX2 paralog complex directly stimulate motor-driven activities of SMARCAL1 through physical interactions. Reconstituted biochemical assays with purified proteins, DNA annealing assay, ATPase translocase assay, branch migration assay, pulldown of physical interactions Nucleic acids research High 35801922
2022 SMARCAL1 and BRG1 directly interact with each other, forming a complex dependent on the ATPase activities of both proteins; the HARP domains of SMARCAL1 mediate interaction with BRG1; SIOD-associated SMARCAL1 mutants and CSS4-associated BRG1 mutants fail to form this complex. Co-immunoprecipitation, deletion mutant analysis, ATPase-dead mutant analysis Frontiers in cell and developmental biology Medium 35784471
2023 SmarcAL1 interacts with ANGPTL3; SmarcAL1 translocates from nucleus to cytoplasmic peroxisomes in response to cell growth states; this translocation modulates gene expression of lipid catabolism genes, and SmarcAL1 loss reduces expression of key cellular lipid catabolism genes. Co-IP/proteomics, subcellular fractionation/immunofluorescence, SMARCAL1 KO cells with lipid gene expression analysis, mouse in vivo models Communications biology Medium 38129665
2024 RFWD3 ubiquitin ligase interacts with SMARCAL1 and directly ubiquitylates it in vitro and following DNA damage in vivo; SMARCAL1 ubiquitylation does not trigger proteasomal degradation but disengages it from RPA, regulating its fork remodeling function; proper RFWD3-mediated SMARCAL1 regulation protects stalled forks from excessive MUS81-mediated cleavage. Proteomics/MS to identify substrates, in vitro ubiquitylation assay, Co-IP, ubiquitylation-defective mutant analysis, MUS81 epistasis, DNA fiber assay PLoS biology High 38502677
2024 SMARCAL1 limits endogenous DNA damage to suppress cGAS-STING-dependent innate immune signaling during cancer cell growth; simultaneously, SMARCAL1 cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, promoting PD-L1 expression; SMARCAL1 loss enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade. SMARCAL1 KO in cancer cells, cGAS-STING pathway reporter assays, ATAC-seq for chromatin accessibility, ChIP for JUN binding, mouse melanoma tumor model, immune checkpoint blockade treatment Cell High 38301646
2024 SMARCAL1 shows profound synthetic lethality with FANCM; combined loss causes severe genome instability linked to chromosome breakage at loci enriched in simple repeats that challenge replication fork progression. CRISPR-based synthetic lethality screen, double-KO cells, chromosome breakage assays, genomic localization analysis Molecular cell Medium 39510066
2024 CSB directly interacts with RPA via an RPA32C-interacting motif that competes with SMARCAL1 for RPA32 binding at stalled forks; CSB and SMARCAL1 act non-redundantly to restrain fork progression under mild replication stress; SMARCAL1 inhibits restart of stalled forks in BRCA2-deficient cells, likely suppressing BIR-mediated repair of collapsed forks. Co-IP of CSB-RPA interaction, RPA32C competition assay, DNA fiber analysis, BRCA2-deficient cell epistasis, drug sensitivity assays Nucleic acids research Medium 38416570
2017 In Drosophila, Marcal1 (SMARCAL1 ortholog) mediates annealing during synthesis-dependent strand annealing (SDSA) at DSBs; Marcal1 null mutants show significantly reduced annealing-dependent repair in both synthesis-dependent and single-strand annealing assays; the ATP-binding activity of Marcal1 is required for this annealing function. Marcal1 null and ATP-binding mutants in Drosophila, genetic DSB repair assays (SDSA and SSA reporter assays) Genetics Medium 28258182
2015 SIOD-associated mutations (A468P, I548N, S579L) in RecA-like domain I of SMARCAL1 abolish ATPase activity and alter secondary structure (α-helix/β-sheet content); these mutations alter DNA-binding affinity in the presence of ATP and increase replication stress in vivo. In vitro ATPase assay with purified mutant proteins, circular dichroism, molecular simulation, fluorescence spectroscopy DNA binding assay, cellular replication stress markers The FEBS journal Medium 26195148
2009 Morpholino knockdown of smarcal1 in zebrafish causes G0/G1 cell cycle arrest, cell apoptosis, and developmental defects (growth retardation, craniofacial abnormality, haematopoietic and vascular defects); SMARCAL1 is transcriptionally repressed by E2F6 as demonstrated by EMSA and reporter assay. Morpholino knockdown in zebrafish, cell cycle analysis, apoptosis assay, EMSA, reporter assay, E2F6 overexpression Developmental biology Medium 20036229

Source papers

Stage 0 corpus · 89 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes & development 340 23873943
2017 Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments. Molecular cell 325 28757209
2012 SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication. Genes & development 257 22279047
2002 Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nature genetics 245 11799392
2009 The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Genes & development 213 19793861
2009 The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart. Genes & development 185 19793862
2017 Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability. Critical reviews in biochemistry and molecular biology 124 28954549
2009 Identification of SMARCAL1 as a component of the DNA damage response. The Journal of biological chemistry 101 19841479
2016 SMARCAL1 Resolves Replication Stress at ALT Telomeres. Cell reports 99 26832416
2024 SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion. Cell 88 38301646
2015 SMARCAL1 maintains telomere integrity during DNA replication. Proceedings of the National Academy of Sciences of the United States of America 80 26578802
2000 Cloning and characterization of HARP/SMARCAL1: a prokaryotic HepA-related SNF2 helicase protein from human and mouse. Genomics 60 10857751
2014 High-affinity DNA-binding domains of replication protein A (RPA) direct SMARCAL1-dependent replication fork remodeling. The Journal of biological chemistry 53 25552480
2008 Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation. Journal of medical genetics 50 18805831
2015 Smarcal1 promotes double-strand-break repair by nonhomologous end-joining. Nucleic acids research 45 26089390
2012 SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo. American journal of medical genetics. Part A 37 22888040
2022 Strand annealing and motor driven activities of SMARCAL1 and ZRANB3 are stimulated by RAD51 and the paralog complex. Nucleic acids research 34 35801922
2014 Structural analysis of replication protein A recruitment of the DNA damage response protein SMARCAL1. Biochemistry 33 24730652
2010 SMARCAL1 and replication stress: an explanation for SIOD? Nucleus (Austin, Tex.) 33 21327070
2019 Smarcal1 and Zranb3 Protect Replication Forks from Myc-Induced DNA Replication Stress. Cancer research 29 30610086
2014 A novel SMARCAL1 mutation associated with a mild phenotype of Schimke immuno-osseous dysplasia (SIOD). BMC nephrology 29 24589093
2013 Identification and characterization of SMARCAL1 protein complexes. PloS one 28 23671665
2008 Neurologic phenotype of Schimke immuno-osseous dysplasia and neurodevelopmental expression of SMARCAL1. Journal of neuropathology and experimental neurology 28 18520775
2011 The HARP domain dictates the annealing helicase activity of HARP/SMARCAL1. EMBO reports 27 21525954
2017 BRG1 and SMARCAL1 transcriptionally co-regulate DROSHA, DGCR8 and DICER in response to doxorubicin-induced DNA damage. Biochimica et biophysica acta. Gene regulatory mechanisms 26 28716689
2013 Schimke Immunoosseous Dysplasia associated with undifferentiated carcinoma and a novel SMARCAL1 mutation in a child. Pediatric blood & cancer 25 23630135
2023 Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells. Neuro-oncology 23 36689342
2020 CSB cooperates with SMARCAL1 to maintain telomere stability in ALT cells. Journal of cell science 23 31974116
2017 The role of SMARCAL1 in replication fork stability and telomere maintenance. DNA repair 21 28623093
2009 SMARCAL1 mutations: a cause of prepubertal idiopathic steroid-resistant nephrotic syndrome. Pediatric research 21 19127206
2005 R561C missense mutation in the SMARCAL1 gene associated with mild Schimke immuno-osseous dysplasia. Pediatric nephrology (Berlin, Germany) 21 16237566
2021 SMARCAL1 loss and alternative lengthening of telomeres (ALT) are enriched in giant cell glioblastoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 19 34103668
2020 SMARCAL1, the annealing helicase and the transcriptional co-regulator. IUBMB life 19 32754981
2014 Structure of RPA32 bound to the N-terminus of SMARCAL1 redefines the binding interface between RPA32 and its interacting proteins. The FEBS journal 19 24910198
2016 Transcriptional Regulation of Atp-Dependent Chromatin Remodeling Factors: Smarcal1 and Brg1 Mutually Co-Regulate Each Other. Scientific reports 18 26843359
2015 SMARCAL1 Negatively Regulates C-Myc Transcription By Altering The Conformation Of The Promoter Region. Scientific reports 18 26648259
2018 Regulation of ATM and ATR by SMARCAL1 and BRG1. Biochimica et biophysica acta. Gene regulatory mechanisms 17 30317028
2008 Schimke immuno-osseous dysplasia: expression of SMARCAL1 in blood and kidney provides novel insight into disease phenotype. Pediatric research 17 18356746
2016 SMARCAL1 and telomeres: Replicating the troublesome ends. Nucleus (Austin, Tex.) 16 27355316
2020 Podocytic infolding in Schimke immuno-osseous dysplasia with novel SMARCAL1 mutations: a case report. BMC nephrology 14 32393263
2019 Inducible SMARCAL1 knockdown in iPSC reveals a link between replication stress and altered expression of master differentiation genes. Disease models & mechanisms 14 31515241
2015 A novel splice site mutation in SMARCAL1 results in aberrant exon definition in a child with Schimke immunoosseous dysplasia. American journal of medical genetics. Part A 14 25943327
2013 Novel SMARCAL1 bi-allelic mutations associated with a chromosomal breakage phenotype in a severe SIOD patient. Journal of clinical immunology 14 24197801
2009 Donor serum SMARCAL1 concentrations predict primary graft dysfunction in cardiac transplantation. Circulation 14 19752368
2019 Adenovirus E1B 55-Kilodalton Protein Targets SMARCAL1 for Degradation during Infection and Modulates Cellular DNA Replication. Journal of virology 13 30996091
2024 SMARCAL1 ubiquitylation controls its association with RPA-coated ssDNA and promotes replication fork stability. PLoS biology 12 38502677
2024 Profound synthetic lethality between SMARCAL1 and FANCM. Molecular cell 12 39510066
2021 LncRNA MT1DP promotes cadmium-induced DNA replication stress by inhibiting chromatin recruitment of SMARCAL1. The Science of the total environment 12 34715232
2009 Deficiency of smarcal1 causes cell cycle arrest and developmental abnormalities in zebrafish. Developmental biology 12 20036229
2013 Phosphorylation of a C-terminal auto-inhibitory domain increases SMARCAL1 activity. Nucleic acids research 11 24150942
2009 Functional genomics of HMGN3a and SMARCAL1 in early mammalian embryogenesis. BMC genomics 11 19393058
2024 Oncogenic functions and therapeutic potentials of targeted inhibition of SMARCAL1 in small cell lung cancer. Cancer letters 10 38697461
2012 Targeting SMARCAL1 as a novel strategy for cancer therapy. Biochemical and biophysical research communications 10 22995303
2024 CSB and SMARCAL1 compete for RPA32 at stalled forks and differentially control the fate of stalled forks in BRCA2-deficient cells. Nucleic acids research 9 38416570
2017 Annealing of Complementary DNA Sequences During Double-Strand Break Repair in Drosophila Is Mediated by the Ortholog of SMARCAL1. Genetics 9 28258182
2017 A novel compound heterozygous mutation of the SMARCAL1 gene leading to mild Schimke immune-osseous dysplasia: a case report. BMC pediatrics 9 29282041
2010 Novel compound mutations of SMARCAL1 associated with severe Schimke immuno-osseous dysplasia in a Chinese patient. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 9 20179009
2019 Whole Exome Sequencing Identified a Novel Biallelic SMARCAL1 Mutation in the Extremely Rare Disease SIOD. Frontiers in genetics 7 31275356
2015 Ligand-induced conformation changes drive ATP hydrolysis and function in SMARCAL1. The FEBS journal 7 26195148
2016 A novel SMARCAL1 missense mutation that affects splicing in a severely affected Schimke immunoosseous dysplasia patient. European journal of medical genetics 6 27282802
2022 Different Phenotypes of Schimke Immuno-Osseous Dysplasia (SIOD) in Two Sisters with the Same Mutation in the SMARCAL1 Gene. Endocrine, metabolic & immune disorders drug targets 5 35209826
2025 HPV16 recruitment of SMARCAL1 to viral and host replication forks is required for the viral life cycle. bioRxiv : the preprint server for biology 4 40777248
2025 Investigation of DNA Damage Response Genes Validates the Role of DNA Repair in Pediatric Cancer Risk and Identifies SMARCAL1 as a Novel Osteosarcoma Predisposition Gene. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 4 41066719
2022 T-cell receptor signaling in Schimke immuno-osseous dysplasia is SMARCAL1-independent. Frontiers in immunology 4 36330520
2024 DNA fork remodeling proteins, Zranb3 and Smarcal1, are uniquely essential for aging hematopoiesis. Aging cell 3 39044358
2023 Chromatin regulator SMARCAL1 modulates cellular lipid metabolism. Communications biology 3 38129665
2022 On the Interaction Between SMARCAL1 and BRG1. Frontiers in cell and developmental biology 3 35784471
2021 A novel compound heterozygous variant in SMARCAL1 leading to mild Schimke immune-osseous dysplasia identified using whole-exome sequencing. The Journal of international medical research 3 33900868
2012 Integrated multiplex ligation dependent probe amplification (MLPA) assays for the detection of alterations in the HEXB, GM2A and SMARCAL1 genes to support the diagnosis of Morbus Sandhoff, M. Tay-Sachs variant AB and Schimke immuno-osseous dysplasia in humans. Molecular and cellular probes 3 23010210
2026 SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use alternative lengthening of telomeres. Neuro-oncology 2 41520142
2024 ALTering Cancer by Triggering Telomere Replication Stress through the Stabilization of Promoter G-Quadruplex in SMARCAL1. ACS chemical biology 2 38959478
2017 Recurrent atypical haemolytic uraemic syndrome post kidney transplant due to a CD46 mutation in the setting of SMARCAL1-mediated inherited kidney disease. Nephrology (Carlton, Vic.) 2 28176476
2026 SMARCAL1 is a new osteosarcoma predisposition gene. Journal of the National Cancer Institute 1 40996338
2025 ANGPTL3 regulates the peroxisomal translocation of SmarcAL1 in response to cell growth states. Scientific reports 1 39934259
2025 Advanced Cancer Immunotherapy via SMARCAL1 Blockade Using a Glucose-Responsive CRISPR Nanovaccine. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 40650655
2024 Loss of helicase C-terminal domain of SMARCAL1 protein associated with severe Schimke immuno-osseous dysplasia. Pathology, research and practice 1 38218042
2024 ANGPTL3 regulates the peroxisomal translocation of SmarcAL1 in response to cell growth states. bioRxiv : the preprint server for biology 1 38895318
2026 The Smarcal1-Usp37 locus modulates glycogen aggregation in astrocytes of the aged hippocampus. Cell systems 0 41633365
2026 Adipose-derived mesenchymal stem cell exosomes enhance diabetic wound healing via the amelioration of fibroblast senescence through the SMARCAL1-Drp1 signaling pathway. Biochimica et biophysica acta. Molecular basis of disease 0 41655540
2026 SMARCAL1 is a candidate therapeutic target for ALT-positive tumors. bioRxiv : the preprint server for biology 0 41757119
2026 Tabular foundation model predicts alternative lengthening of telomeres (ALT) and identifies SMARCAL1 as a target in ALT-driven cancers. bioRxiv : the preprint server for biology 0 41847032
2026 HPV16 recruitment of SMARCAL1 to viral and host replication forks is required for the viral life cycle. mBio 0 41910319
2025 Comprehensive investigation of DNA damage repair genes in children with cancer identifies SMARCAL1 as novel osteosarcoma predisposition gene. medRxiv : the preprint server for health sciences 0 40463577
2025 Copy number variation: an important genetic mechanism in SMARCAL1-related immunoosseous dysplasia (Schimke type) in Indian patients. Journal of genetics 0 41568729
2024 Feeding two birds with one scone: The dual roles of SMARCAL1 in antitumor immunity. Molecular cell 0 38458172
2024 WITHDRAWN: Strand dependent bypass of DNA lesions during fork reversal by ATP-dependent translocases SMARCAL1, ZRANB3, and HLTF. bioRxiv : the preprint server for biology 0 39345618
2023 Generation of an induced pluripotent stem cell line (SDASi001-A) from a Schimke immune-osseous dysplasia patient with SMARCAL1 mutations. Stem cell research 0 37788557
2019 [SMARCAL1, roles and mechanisms in genome stability maintenance]. Yi chuan = Hereditas 0 31857280
2015 [SMARCAL1 gene analysis of 2 Chinese Schimke immuno-osseous dysplasia children]. Zhonghua er ke za zhi = Chinese journal of pediatrics 0 25748404

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