Affinage

SMARCAL1

SNF2 related chromatin remodeling annealing helicase 1 · UniProt Q9NZC9

Length
954 aa
Mass
105.9 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMARCAL1 is an SNF2-family ATP-dependent annealing helicase and DNA translocase that maintains genome stability by catalyzing replication fork regression, branch migration, and reannealing of RPA-coated single-stranded DNA at stalled replication forks (PMID:18974355, PMID:22279047, PMID:35801922). It is recruited to stalled forks and DNA damage sites through a direct N-terminal interaction with RPA32C, where its fork-remodeling activity is positively regulated by S889 phosphorylation (relieving C-terminal autoinhibition) and negatively regulated by ATR-mediated S652 phosphorylation (preventing excessive regression and SLX4-dependent fork cleavage) and by RFWD3-mediated ubiquitylation (disengaging it from RPA) (PMID:19793861, PMID:24150942, PMID:23873943, PMID:38502677). SMARCAL1 additionally maintains telomere integrity during replication, suppresses cGAS-STING innate immune signaling by limiting endogenous DNA damage, and cooperates with JUN to sustain PD-L1 expression through chromatin accessibility (PMID:26578802, PMID:38301646). Loss-of-function mutations in SMARCAL1 cause Schimke immuno-osseous dysplasia (PMID:11799392).

Mechanistic history

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

    Establishing that SMARCAL1 possesses intrinsic enzymatic activity answered whether this SNF2-family member functions as a DNA-dependent ATPase, providing the biochemical foundation for all subsequent mechanistic work.

    Evidence In vitro ATPase assay with purified recombinant SMARCAL1 protein

    PMID:10857751

    Open questions at the time
    • Single lab, single method
    • Substrate specificity and biological function of ATPase activity unknown
    • No structural information
  2. 2002 High

    Positional cloning in 26 SIOD families established SMARCAL1 as the causative gene for Schimke immuno-osseous dysplasia, providing the first link between this remodeler and human disease and demonstrating that missense mutations retain partial function.

    Evidence Genome-wide linkage mapping, positional cloning, and mutation analysis in 26 families

    PMID:11799392

    Open questions at the time
    • Molecular mechanism by which SMARCAL1 loss causes SIOD pathology unknown
    • No functional assay for disease alleles yet available
  3. 2008 High

    Discovering that SMARCAL1 is an annealing helicase—rewinding RPA-coated ssDNA bubbles in an ATP-dependent manner—defined a unique enzymatic activity not shared by other SNF2 proteins and explained how SIOD mutations cause loss of function.

    Evidence In vitro annealing helicase assay with RPA-coated substrates; SIOD mutant analysis; comparison with Rad54

    PMID:18805831 PMID:18974355

    Open questions at the time
    • Physiological substrate (replication fork vs. transcription bubble) not yet identified
    • Mechanism of annealing activity at molecular level unclear
  4. 2009 High

    Multiple independent groups simultaneously demonstrated that SMARCAL1 is recruited to stalled forks through a direct N-terminal RPA32C-binding motif and is phosphorylated by ATM/ATR/DNA-PK during replication stress, establishing the recruitment and regulatory framework for its fork-protective function.

    Evidence Reciprocal Co-IP, domain mapping, laser micro-irradiation, live-cell imaging, mass spectrometry phosphoproteomics, Xenopus egg extracts across four independent labs

    PMID:19793861 PMID:19793862 PMID:19793863 PMID:19793864 PMID:19841479

    Open questions at the time
    • Specific phosphorylation sites and their functional consequences not yet mapped
    • Mechanism of fork protection downstream of recruitment unknown
  5. 2011 High

    Chimera experiments showed that the tandem HARP (2HP) domain is necessary and sufficient to confer annealing helicase activity on heterologous SNF2 ATPase domains, pinpointing the substrate-recognition determinant.

    Evidence HARP-SNF2 chimera construction with in vitro annealing helicase assay and cellular complementation

    PMID:21525954

    Open questions at the time
    • How the HARP domain recognizes substrates structurally unknown
    • Whether HARP domain has functions beyond annealing helicase activity not tested
  6. 2012 High

    Reconstitution of fork regression and Holliday junction branch migration activities on model fork substrates established SMARCAL1 as a bona fide fork reversal enzyme, with the HARP2-ATPase core forming the catalytic unit; loss of SMARCAL1 was shown to cause MUS81-dependent DSBs.

    Evidence In vitro fork regression/branch migration assays, SAXS structural characterization, mutagenesis, siRNA with MUS81 epistasis

    PMID:22279047

    Open questions at the time
    • No high-resolution structure of full-length enzyme on a fork substrate
    • How SMARCAL1 selects stalled forks versus other branched structures unclear
  7. 2013 High

    Two opposing regulatory phosphorylation events were defined: ATR-mediated S652 phosphorylation restrains SMARCAL1 to prevent excessive fork regression and SLX4/CtIP-dependent collapse, while S889 phosphorylation relieves C-terminal autoinhibition to activate the enzyme, revealing a phosphorylation-based rheostat controlling fork remodeling.

    Evidence Mass spectrometry phosphosite identification, phosphomimetic/non-phosphorylatable mutants, in vitro ATPase/fork regression assays, DNA fiber assays, Xenopus system, epistasis with SLX4/CtIP

    PMID:23873943 PMID:24150942

    Open questions at the time
    • Kinase responsible for S889 phosphorylation unidentified
    • Temporal coordination of activating and inhibitory phosphorylation events in vivo unclear
  8. 2013 High

    Proteomics revealed that SMARCAL1 forms complexes with DNA-PKcs and WRN (the latter indirectly via RPA), and epistasis experiments showed SMARCAL1 and WRN act in distinct fork-protective pathways converging on prevention of MUS81 cleavage.

    Evidence Mass spectrometry interactome, Co-IP, immunofluorescence co-localization, in vitro fork regression, siRNA epistasis

    PMID:23671665

    Open questions at the time
    • Molecular basis for functional distinction between SMARCAL1 and WRN fork regression unclear
    • Role of DNA-PKcs in regulating SMARCAL1 not dissected
  9. 2014 High

    A crystal structure of the SMARCAL1 RPA-binding motif bound to RPA32C at 1.4 Å resolution, combined with demonstration that RPA DBD-A/B near the fork junction activate SMARCAL1, provided the first structural framework for how RPA both recruits and allosterically activates SMARCAL1 at stalled forks.

    Evidence X-ray crystallography (PDB 4MQV), ITC, NMR, mutagenesis, in vitro fork remodeling with RPA domain mutants

    PMID:24730652 PMID:24910198 PMID:25552480

    Open questions at the time
    • No structure of SMARCAL1 catalytic domains bound to a fork substrate
    • How DBD-A/B positioning at the fork junction allosterically stimulates SMARCAL1 ATPase unknown
  10. 2015 High

    SMARCAL1 was shown to maintain telomere stability during replication independently of its RPA-binding motif and to promote NHEJ by facilitating Ku70/DNA-PKcs and XRCC4 recruitment, expanding its roles beyond fork reversal.

    Evidence KO/siRNA in multiple cell lines, C-circle assay, complementation with RPA-binding mutants, G1-phase irradiation, NHEJ factor immunofluorescence, domain mutagenesis

    PMID:26089390 PMID:26578802

    Open questions at the time
    • Mechanism of telomere protection independent of RPA binding not defined
    • How SMARCAL1 promotes NHEJ factor recruitment mechanistically unknown
  11. 2017 High

    Immunodepletion in Xenopus extracts demonstrated that SMARCAL1-mediated fork reversal converts ssDNA-gap-containing forks (arising from BRCA2/RAD51 deficiency) into reversed forks that become substrates for MRE11-dependent nascent DNA degradation, placing SMARCAL1 as a key upstream step in the fork degradation pathway.

    Evidence Xenopus egg extract biochemistry, SMARCAL1 immunodepletion, electron microscopy of replication intermediates, in vitro MRE11 degradation assay

    PMID:28757209

    Open questions at the time
    • Whether this mechanism operates identically in mammalian cells not directly shown at the EM level
    • How cells select between protective and degradative outcomes at reversed forks remains unclear
  12. 2022 High

    Biochemical reconstitution revealed that SMARCAL1 possesses an ATP-independent RPA-dependent strand-annealing activity distinct from its ATPase-driven fork reversal, and that RAD51 and the BCDX2 paralog complex directly stimulate SMARCAL1 motor activity through physical interaction, adding a new layer of regulation.

    Evidence Reconstituted annealing, ATPase, and fork remodeling assays; Co-IP/pulldown with RAD51 and BCDX2

    PMID:35801922

    Open questions at the time
    • Structural basis for RAD51/BCDX2 stimulation of SMARCAL1 unknown
    • Relative contributions of ATP-independent annealing versus ATP-dependent translocation in vivo unclear
  13. 2024 High

    Three studies expanded SMARCAL1 biology: RFWD3 ubiquitylates SMARCAL1 non-degradatively to disengage it from RPA at forks, SMARCAL1 suppresses cGAS-STING signaling and cooperates with JUN to maintain PD-L1 chromatin accessibility, and combined SMARCAL1/FANCM loss reveals synthetic lethality with genome instability at simple repeat loci.

    Evidence In vitro ubiquitylation reconstitution, Co-IP, MUS81 cleavage assays; SMARCAL1 KO with cGAS-STING reporters, ATAC-seq, ChIP, mouse melanoma model; CRISPR synthetic lethality screen, double-KO cytogenetics

    PMID:38301646 PMID:38502677 PMID:39510066

    Open questions at the time
    • Ubiquitylation sites on SMARCAL1 and how they specifically disrupt RPA binding not structurally defined
    • Mechanism by which SMARCAL1 maintains chromatin accessibility at PD-L1 locus (remodeling vs. fork protection) not distinguished
    • Molecular basis for SMARCAL1-FANCM functional redundancy at repeats unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of full-length SMARCAL1 engaged with a replication fork substrate, the identity of the kinase phosphorylating S889, how SMARCAL1 protects telomeres independently of RPA binding, and the precise mechanism by which SMARCAL1 loss causes the multi-organ pathology of Schimke immuno-osseous dysplasia.
  • No cryo-EM or crystal structure of SMARCAL1 on a fork substrate
  • S889 kinase unidentified
  • RPA-independent telomere protection mechanism undefined
  • Pathophysiological link between fork instability and SIOD tissue-specific phenotypes not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 6 GO:0003677 DNA binding 4 GO:0140097 catalytic activity, acting on DNA 3
Localization
GO:0005694 chromosome 4 GO:0005654 nucleoplasm 3
Pathway
R-HSA-69306 DNA Replication 5 R-HSA-73894 DNA Repair 5 R-HSA-1640170 Cell Cycle 3 R-HSA-168256 Immune System 1
Partners
MUS81PRKDCRAD51RFWD3RPA1RPA2WRN

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 HARP/SMARCAL1 is an ATP-dependent annealing helicase that rewinds single-stranded DNA bubbles stably bound by RPA; SIOD-associated mutations abolish this annealing helicase activity, and other SNF2 ATPases (e.g., Rad54) lack this activity. In vitro biochemical assay (annealing helicase assay with RPA-coated ssDNA bubbles); mutagenesis of SIOD-associated alleles Science High 18974355
2009 SMARCAL1 interacts directly with RPA and is recruited to stalled replication forks and sites of DNA damage in an RPA-dependent manner; an N-terminal RPA-binding motif (similar to TIPIN) is necessary and sufficient for fork targeting, but not required for annealing helicase activity in vitro; loss of SMARCAL1 causes increased RPA chromatin loading and persistent RPA phosphorylation after replication stress. Direct binding assay (Co-IP, pulldown), siRNA knockdown, live-cell imaging/immunofluorescence, functional genomic screen Genes & development High 19793861 19793862 19793864 19841479
2009 SMARCAL1 is phosphorylated in a caffeine-sensitive (ATM/ATR-dependent) manner in response to DSBs and stalled replication forks; ATM, ATR, and DNA-PK all phosphorylate SMARCAL1 in response to replication stress. Mass spectrometry phosphoproteomics, Xenopus egg extract assays, pharmacological inhibition (caffeine) Genes & development / Journal of Biological Chemistry High 19793861 19841479
2009 The N-terminal RPA-binding motif of HARP/SMARCAL1 is necessary and sufficient to recruit it to laser-induced DNA damage sites; this motif is not required for annealing helicase activity. Laser micro-irradiation/live-cell imaging, domain deletion/mutation analysis Genes & development High 19793863
2012 SMARCAL1 catalyzes fork regression and Holliday junction branch migration on model replication fork substrates; its HARP2 domain is essential for substrate binding and activity; HARP2 and ATPase domains fold into a compact core enzymatic unit; SIOD mutations and HARP2 domain mutations abrogate these activities; absence of SMARCAL1 leads to MUS81-dependent DSB formation. In vitro fork regression/branch migration assays, limited proteolysis, small-angle X-ray scattering (SAXS), homology modeling, mutagenesis, siRNA knockdown with DSB readout (MUS81 dependence) Genes & development High 22279047
2000 Purified HARP/SMARCAL1 protein exhibits single-stranded DNA-dependent ATPase activity, consistent with SNF2 family membership. In vitro ATPase assay with purified His-tagged recombinant protein Genomics Medium 10857751
2002 Mutations in SMARCAL1 (nonsense, frameshift, splice, and missense) cause Schimke immuno-osseous dysplasia; missense mutations retain partial function and cause milder disease, indicating genotype-phenotype correlation. Genome-wide linkage mapping, positional cloning, mutation analysis in 26 families Nature genetics High 11799392
2013 ATR phosphorylates SMARCAL1 on S652, limiting its fork regression activities; unregulated SMARCAL1 (when ATR is inhibited) contributes to fork collapse via SLX4-dependent cleavage and CtIP-dependent resection; this mechanism operates in both mammalian and Xenopus systems. Selective ATR inhibitors, mass spectrometry phosphosite identification, phosphomimetic/non-phosphorylatable mutants, DNA fiber assays, Xenopus system, siRNA knockdown epistasis Genes & development High 23873943
2013 Phosphorylation of SMARCAL1 at S889 (by an unspecified kinase, present in undamaged cells) relieves an auto-inhibitory C-terminal domain, increasing DNA-stimulated ATPase activity and fork regression activity; phosphomimetic S889D is hyperactive in vitro and in cells; deletion of the C-terminal region similarly creates a hyperactive enzyme. Mass spectrometry phosphosite mapping, in vitro ATPase and fork regression assays with phosphomimetic/non-phosphorylatable mutants, cellular complementation assays Nucleic acids research High 24150942
2013 SMARCAL1 forms complexes with DNA-PKcs and WRN helicase; the SMARCAL1–WRN interaction is indirect and mediated by RPA as a scaffold; SMARCAL1 and WRN co-localize at stalled forks independently of one another and act in distinct pathways to prevent MUS81 cleavage; SMARCAL1 catalyzes fork regression more efficiently than WRN and independently of it. Proteomics/mass spectrometry interactome, Co-IP, immunofluorescence co-localization, in vitro fork regression assays, siRNA epistasis PloS one High 23671665
2014 RPA high-affinity DNA-binding domains A and B (DBD-A/B) near the fork junction activate SMARCAL1 fork remodeling; an interaction between SMARCAL1 and RPA is essential for SMARCAL1 activation; the location of the interacting surface on RPA is not critical; DBD-C and DBD-D are not required for SMARCAL1 regulation. In vitro fork remodeling assays with RPA DBD mutants, biochemical reconstitution Journal of Biological Chemistry High 25552480
2014 Crystal structure of RPA32C bound to a 26-aa peptide from the SMARCAL1 N-terminus (RBM) reveals a 1:1 complex in which SMARCAL1 RBM adopts an α-helical conformation; 11 conserved residues on one face contact RPA32C; RPA32C undergoes conformational rearrangement (α1/α2 loop) upon binding; Kd ≈ 2.5 µM by ITC. X-ray crystallography (1.4 Å, PDB 4MQV), ITC, NMR chemical shift perturbation, mutagenesis The FEBS journal / Biochemistry High 24730652 24910198
2011 The conserved tandem HARP (2HP) domain dictates the ATP-dependent annealing helicase activity of SMARCAL1; chimeric proteins fusing the 2HP domain of SMARCAL1 to the SNF2 domain of BRG1 or HELLS acquire annealing helicase activity in vitro and can mimic SMARCAL1 function at replication forks in vivo. Domain deletion/chimera construction, in vitro annealing helicase assay, cellular complementation at stalled forks EMBO reports High 21525954
2008 SIOD-associated SMARCAL1 mutations impair protein expression, stability, subcellular localization, chromatin binding, and ATPase enzymatic activity; SMARCAL1 binds chromatin in vivo; disease severity in Drosophila correlates inversely with overall SMARCAL1 activity. Chromatin fractionation, subcellular localization imaging, ATPase assays of SIOD mutants, Drosophila in vivo expression Journal of medical genetics Medium 18805831
2015 SMARCAL1 maintains telomere stability during replication; SMARCAL1-deficient cells accumulate telomere-associated DNA damage and extrachromosomal telomere circles (C-circles) but do not display other ALT hallmarks; this telomere function does not require RPA interaction and is not shared by ZRANB3 or HLTF, indicating a unique role. siRNA/gene knockout, DNA damage immunofluorescence, C-circle assay, complementation with RPA-binding mutants PNAS High 26578802
2016 SMARCAL1 associates with ALT telomeres to resolve replication stress; in the absence of SMARCAL1, persistently stalled forks at ALT telomeres deteriorate into DSBs promoting chromosome fusions. Co-immunoprecipitation/ChIP at telomeres, siRNA depletion, telomere FISH, DSB/fusion assays Cell reports Medium 26832416
2017 Smarcal1-mediated fork reversal in Xenopus laevis is required to convert forks with ssDNA gaps (arising from Brca2 deficiency and reduced Rad51 binding) into reversed forks, which then undergo Mre11-dependent nascent DNA degradation; stable Rad51 nucleofilaments directly prevent Mre11-dependent degradation at reversed forks. Xenopus laevis egg extract biochemistry, isolation of Xenopus Brca2, Smarcal1 immunodepletion, electron microscopy of fork structures, in vitro Mre11 degradation assay Molecular cell High 28757209
2015 Smarcal1 promotes non-homologous end joining (NHEJ) of DSBs; SMARCAL1-deficient cells (chicken DT40 and human TK6) are sensitive to topoisomerase II inhibitors and exhibit increased radiosensitivity in G1; both ATPase domain inactivation and RPA-binding site deletion phenocopy null mutation; SMARCAL1 loss impairs Ku70/DNA-PKcs and XRCC4 accumulation at damage sites. Gene disruption (KO) in two cell lines, clonogenic survival, G1-phase irradiation, immunofluorescence of NHEJ factors, domain mutagenesis Nucleic acids research High 26089390
2022 SMARCAL1 uniquely anneals RPA-coated ssDNA in an RPA-interaction-dependent but ATP-independent reaction; SMARCAL1 and ZRANB3 (but not HLTF) use ATPase-driven translocase activity to rezip RPA-covered bubbled DNA mimicking fork reversal; RAD51 and the RAD51 paralog complex BCDX2 directly stimulate the motor activities of SMARCAL1 and ZRANB3 via physical interactions. Reconstituted biochemical assays (annealing, ATPase, fork remodeling), Co-IP/pulldown to establish physical interactions with RAD51/BCDX2 Nucleic acids research High 35801922
2024 RFWD3 ubiquitin ligase interacts with and ubiquitylates SMARCAL1 directly in vitro and following DNA damage in vivo; ubiquitylation does not trigger proteasomal degradation but instead disengages SMARCAL1 from RPA at stalled forks, limiting excessive MUS81-mediated fork cleavage. Proteomics to identify RFWD3 substrates, in vitro ubiquitylation reconstitution, Co-IP, proteasome inhibition controls, MUS81-cleavage/fork stability assays PLoS biology High 38502677
2024 SMARCAL1 suppresses cGAS-STING-dependent innate immune signaling by limiting endogenous DNA damage; simultaneously it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby sustaining PD-L1 expression in cancer cells. SMARCAL1 KO, cGAS-STING reporter assays, ATAC-seq, ChIP for JUN and chromatin accessibility at PD-L1 locus, mouse melanoma immune challenge model Cell High 38301646
2024 SMARCAL1 displays a profound synthetic-lethal interaction with FANCM translocase; combined loss causes severe genome instability including chromosome breakage enriched at simple repeat loci, defining a genetic buffering mechanism for maintaining genome integrity at repetitive sequences. CRISPR-based synthetic lethality screens, double-KO cell lines, DNA fiber assays, cytogenetics Molecular cell High 39510066
2019 Adenovirus E1B-55K targets SMARCAL1 for proteasomal degradation via a cullin RING ligase; SMARCAL1 is phosphorylated at S123, S129, and S173 in an ATR- and CDK-dependent manner early during infection, promoting its recruitment to viral replication centers and its subsequent degradation; E1B-55K expression initially enhances cellular replication fork speed but ultimately increases fork stalling. Adenovirus infection system, siRNA/inhibitor of ATR and CDK, proteasome inhibitors, immunofluorescence at viral replication centers, DNA fiber assays, Co-IP with E1B-55K Journal of virology Medium 30996091
2015 SMARCAL1 binds to the c-myc promoter and uses ATP hydrolysis (using a specific upstream c-myc promoter region as DNA effector) to alter promoter DNA conformation, thereby negatively regulating c-myc transcription; BRG1 and SMARCAL1 are co-localized on the c-myc promoter with RNAPII. ChIP, EMSA, reporter assay, in vitro ATPase assay with c-myc promoter DNA as effector Scientific reports Low 26648259
2009 Morpholino knockdown of smarcal1 in zebrafish causes G0/G1 cell cycle arrest, apoptosis, and developmental abnormalities (growth retardation, craniofacial abnormality, hematopoietic/vascular defects) recapitulating SIOD; SMARCAL1 transcription is repressed by E2F6 binding to its promoter. Morpholino knockdown in zebrafish, cell cycle analysis, EMSA and reporter assay for E2F6 regulation Developmental biology Medium 20036229
2021 The lncRNA MT1DP is induced by Cd/ATR/HIF-1α signaling and binds to SMARCAL1 on chromatin, competitively inhibiting SMARCAL1 interaction with RPA, leading to increased replication stress and DNA damage. RNA-protein pulldown/Co-IP, siRNA knockdown, chromatin fractionation, RPA interaction assay, DNA fiber analysis Science of the Total Environment Low 34715232
2017 BRG1 and SMARCAL1 co-regulate transcription of DROSHA, DGCR8, and DICER in response to doxorubicin-induced DSBs; loss of SMARCAL1 specifically reduces DROSHA transcription and impairs 53BP1 foci formation, which can be rescued by ncRNA from damaged cells. siRNA knockdown, ChIP, RT-qPCR, 53BP1 foci immunofluorescence, ncRNA rescue experiments Biochimica et biophysica acta Low 28716689
2017 Drosophila Marcal1 (ortholog of SMARCAL1) mediates annealing during synthesis-dependent strand annealing (SDSA) repair of DSBs; null and ATP-binding mutants both reduce annealing-dependent repair, demonstrating that translocation along DNA is required for annealing activity in vivo. Drosophila genetics, SDSA/SSA assay, Marcal1 null and ATPase mutant analysis Genetics Medium 28258182
2020 CSB and SMARCAL1 cooperate at ALT telomeres: CSB promotes HR repair proteins while SMARCAL1 mediates fork regression; combined loss of CSB and SMARCAL1 depletion synergistically increases telomeric MUS81 recruitment and fragile telomere formation, indicating epistasis in fork protection. siRNA double depletion, ChIP at telomeres, immunofluorescence, telomere fragility assay Journal of cell science Medium 31974116

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes & development 336 23873943
2017 Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments. Molecular cell 316 28757209
2012 SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication. Genes & development 253 22279047
2002 Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nature genetics 242 11799392
2009 The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Genes & development 211 19793861
2009 The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart. Genes & development 180 19793862
2010 A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). American journal of respiratory and critical care medicine 167 20870757
2005 First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. American journal of kidney diseases : the official journal of the National Kidney Foundation 153 15754269
2008 HARP is an ATP-driven annealing helicase. Science (New York, N.Y.) 145 18974355
2009 The annealing helicase HARP protects stalled replication forks. Genes & development 123 19793864
2017 Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability. Critical reviews in biochemistry and molecular biology 121 28954549
2009 The annealing helicase HARP is recruited to DNA repair sites via an interaction with RPA. Genes & development 113 19793863
2012 The HARP-like domain-containing protein AH2/ZRANB3 binds to PCNA and participates in cellular response to replication stress. Molecular cell 104 22705370
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 97 26832416
2010 Playing the "Harp": evolution of our understanding of hrp/hrc genes. Annual review of phytopathology 88 20455697
2015 SMARCAL1 maintains telomere integrity during DNA replication. Proceedings of the National Academy of Sciences of the United States of America 79 26578802
2006 The second United Kingdom Heart and Renal Protection (UK-HARP-II) Study: a randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD. American journal of kidney diseases : the official journal of the National Kidney Foundation 79 16490616
2024 SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion. Cell 78 38301646
2002 HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology 70 12058097
2000 Cloning and characterization of HARP/SMARCAL1: a prokaryotic HepA-related SNF2 helicase protein from human and mouse. Genomics 59 10857751
2014 High-affinity DNA-binding domains of replication protein A (RPA) direct SMARCAL1-dependent replication fork remodeling. The Journal of biological chemistry 52 25552480
2001 HARP induces angiogenesis in vivo and in vitro: implication of N or C terminal peptides. Biochemical and biophysical research communications 52 11264008
2008 Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation. Journal of medical genetics 47 18805831
1999 Glycosaminoglycans differentially bind HARP and modulate its biological activity. The Journal of biological chemistry 47 10075664
2015 Smarcal1 promotes double-strand-break repair by nonhomologous end-joining. Nucleic acids research 45 26089390
2011 Alterations of overused supraspinatus tendon: a possible role of glycosaminoglycans and HARP/pleiotrophin in early tendon pathology. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 42 21688311
2012 SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo. American journal of medical genetics. Part A 37 22888040
2003 Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic. Neurology 37 14638969
2000 Effect of a low-Fat diet on body composition and blubber fatty acids of captive juvenile harp seals (Phoca groenlandica). Physiological and biochemical zoology : PBZ 36 10685906
2016 Performance of careHPV for detecting high-grade cervical intraepithelial neoplasia among women living with HIV-1 in Burkina Faso and South Africa: HARP study. British journal of cancer 35 27434037
2022 Strand annealing and motor driven activities of SMARCAL1 and ZRANB3 are stimulated by RAD51 and the paralog complex. Nucleic acids research 33 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
1995 Acanthocytosis, retinitis pigmentosa, and pallidal degeneration: a report of three patients, including the second reported case with hypoprebetalipoproteinemia (HARP syndrome). Neurology 32 7898702
2017 Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 30 27646835
2000 Endothelial cell proliferation induced by HARP: implication of N or C terminal peptides. Biochemical and biophysical research communications 30 10903925
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
2008 Neurologic phenotype of Schimke immuno-osseous dysplasia and neurodevelopmental expression of SMARCAL1. Journal of neuropathology and experimental neurology 28 18520775
2006 Hematology and serum chemistry of harp (Phoca groenlandica) and hooded seals (Cystophora cristata) during the breeding season, in the Gulf of St. Lawrence, Canada. Journal of wildlife diseases 28 16699154
2002 Dominant negative effectors of heparin affin regulatory peptide (HARP) angiogenic and transforming activities. The Journal of biological chemistry 28 12070152
2013 Identification and characterization of SMARCAL1 protein complexes. PloS one 27 23671665
2011 The HARP domain dictates the annealing helicase activity of HARP/SMARCAL1. EMBO reports 27 21525954
2003 Retinal topography of the harp seal Pagophilus groenlandicus. Brain, behavior and evolution 27 14573995
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 25 28716689
2013 Schimke Immunoosseous Dysplasia associated with undifferentiated carcinoma and a novel SMARCAL1 mutation in a child. Pediatric blood & cancer 25 23630135
2002 Transfer of polychlorinated biphenyls and chlorinated pesticides from mother to pup in relation to cytochrome P450 enzyme activities in harp seals (Phoca groenlandica) from the gulf of St. Lawrence, Canada. Environmental toxicology and chemistry 25 11804067
2023 Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells. Neuro-oncology 22 36689342
2020 CSB cooperates with SMARCAL1 to maintain telomere stability in ALT cells. Journal of cell science 22 31974116
2010 Giardia and Cryptosporidium in harp and hooded seals from the Gulf of St. Lawrence, Canada. Veterinary parasitology 21 20594649
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
1999 Glycosaminoglycans promote HARP/PTN dimerization. Biochemical and biophysical research communications 21 10600521
2010 Development of aerobic and anaerobic metabolism in cardiac and skeletal muscles from harp and hooded seals. The Journal of experimental biology 20 20154189
1997 Cellular distribution of the angiogenic factor heparin affin regulatory peptide (HARP) mRNA and protein in the human mammary gland. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20 9283611
2019 Har-P, a short P-element variant, weaponizes P-transposase to severely impair Drosophila development. eLife 19 31845649
2017 The role of SMARCAL1 in replication fork stability and telomere maintenance. DNA repair 19 28623093
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
2007 A basic peptide derived from the HARP C-terminus inhibits anchorage-independent growth of DU145 prostate cancer cells. Experimental cell research 19 17727841
2004 Harp (harmonin-interacting, ankyrin repeat-containing protein), a novel protein that interacts with harmonin in epithelial tissues. Genes to cells : devoted to molecular & cellular mechanisms 19 15461667
2016 Transcriptional Regulation of Atp-Dependent Chromatin Remodeling Factors: Smarcal1 and Brg1 Mutually Co-Regulate Each Other. Scientific reports 18 26843359
2020 SMARCAL1, the annealing helicase and the transcriptional co-regulator. IUBMB life 17 32754981
2018 Regulation of ATM and ATR by SMARCAL1 and BRG1. Biochimica et biophysica acta. Gene regulatory mechanisms 17 30317028
2015 SMARCAL1 Negatively Regulates C-Myc Transcription By Altering The Conformation Of The Promoter Region. Scientific reports 17 26648259
2008 Schimke immuno-osseous dysplasia: expression of SMARCAL1 in blood and kidney provides novel insight into disease phenotype. Pediatric research 17 18356746
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 16 34103668
2020 HARP: a database of structural impacts of systematic missense mutations in drug targets of Mycobacterium leprae. Computational and structural biotechnology journal 16 33304465
1997 Temporal trends in antibody production in captive grey, harp and hooded seals to a single administration immunocontraceptive vaccine. Journal of reproductive immunology 16 9373858
2016 SMARCAL1 and telomeres: Replicating the troublesome ends. Nucleus (Austin, Tex.) 15 27355316
2002 Reference values for serum biochemical parameters in free-ranging harp seals. Veterinary clinical pathology 15 12189594
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
2004 Endogenous glycogen prevents Ca2+ overload and hypercontracture in harp seal myocardial cells during simulated ischemia. Journal of molecular and cellular cardiology 14 15242734
1996 Energetics of lactation in harp seals (Phoca groenlandica) from the Gulf of St. Lawrence, Canada. Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology 14 8870260
2009 Donor serum SMARCAL1 concentrations predict primary graft dysfunction in cardiac transplantation. Circulation 13 19752368
2021 LncRNA MT1DP promotes cadmium-induced DNA replication stress by inhibiting chromatin recruitment of SMARCAL1. The Science of the total environment 12 34715232
2019 Adenovirus E1B 55-Kilodalton Protein Targets SMARCAL1 for Degradation during Infection and Modulates Cellular DNA Replication. Journal of virology 12 30996091
2009 Deficiency of smarcal1 causes cell cycle arrest and developmental abnormalities in zebrafish. Developmental biology 12 20036229
2004 Upregulation of HARP during in vitro myogenesis and rat soleus muscle regeneration. Journal of muscle research and cell motility 12 15160487
2002 Isolation of two cytochrome P450 cDNAs, CYP1A1 and CYP1A2, from harp seal (Phoca groenlandica) and grey seal (Halichoerus grypus). Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 12 12106895
1984 Purification and characterization of a chymosinlike protease from the gastric mucosa of harp seal (Pagophilus groenlandicus). Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire 12 6437645
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2014 Shifts in thermoregulatory strategy during ontogeny in harp seals (Pagophilus groenlandicus). Journal of thermal biology 11 25086979
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
1979 Effects of handling stress on plasma enzymes in harp seals, Phoca groenlandica. Journal of wildlife diseases 11 42815
2024 Profound synthetic lethality between SMARCAL1 and FANCM. Molecular cell 10 39510066
2021 Costs and cost-effectiveness of cervical cancer screening strategies in women living with HIV in Burkina Faso: The HPV in Africa Research Partnership (HARP) study. PloS one 10 33765011
2012 Targeting SMARCAL1 as a novel strategy for cancer therapy. Biochemical and biophysical research communications 10 22995303
2009 Molecular identification of prey in the stomach contents of Harp Seals (Pagophilus groenlandicus) using species-specific oligonucleotides. Molecular ecology resources 10 21565007
2001 The angiogenic factor heparin affin regulatory peptide (HARP) induces proliferation of human peripheral blood mononuclear cells. Cellular and molecular biology (Noisy-le-Grand, France) 10 11936877
1989 Chemical modification and composition of tetrameric isozyme K of alkaline phosphatase from harp seal intestinal mucosa. Comparative biochemistry and physiology. B, Comparative biochemistry 10 2706930
2024 SMARCAL1 ubiquitylation controls its association with RPA-coated ssDNA and promotes replication fork stability. PLoS biology 9 38502677
2017 Annealing of Complementary DNA Sequences During Double-Strand Break Repair in Drosophila Is Mediated by the Ortholog of SMARCAL1. Genetics 9 28258182
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
2017 A novel compound heterozygous mutation of the SMARCAL1 gene leading to mild Schimke immune-osseous dysplasia: a case report. BMC pediatrics 8 29282041
2014 The annealing helicase and branch migration activities of Drosophila HARP. PloS one 8 24866343