Affinage

HLTF

DNA-dependent ATPase/E3 ubiquitin-protein ligase HLTF · UniProt Q14527

Length
1009 aa
Mass
113.9 kDa
Annotated
2026-06-10
79 papers in source corpus 44 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HLTF is a multifunctional SWI/SNF-family enzyme that acts as a human Rad5 ortholog at the center of DNA damage tolerance during replication, combining an N-terminal HIRAN domain, a SWI/SNF ATPase/translocase motor, and a RING E3 ubiquitin ligase domain into a single coordinated activity (PMID:18316726, PMID:18719106, PMID:26051180, PMID:25858588, PMID:19948885). Its RING domain catalyzes Lys-63-linked polyubiquitination of PCNA at Lys-164 in concert with the Rad6-Rad18 and Mms2-Ubc13 ubiquitin-conjugating machinery to drive error-free postreplication repair (PMID:18316726, PMID:18719106); this ligase reaction is recruited and modulated by HIRAN-dependent binding to stalled primer ends and is coupled to RAD6-RAD18-mediated PCNA monoubiquitination (PMID:30335157). The HIRAN domain is an OB-fold that specifically recognizes 3'-OH single-stranded DNA ends, binds the 3'-hydroxyl and locally unwinds the duplex, thereby recruiting HLTF to stalled forks and providing directional guidance for the translocase during fork regression (PMID:26051180, PMID:25858588, PMID:31960921). The ATPase/translocase motor independently reverses replication forks, clears DNA-binding proteins such as RPA, PCNA and RFC from stalled forks, and requires ATP-induced dimerization for productive unwinding (PMID:19948885, PMID:21795603, PMID:42030070). HLTF determines fork remodeling choice in cells: its loss redirects stressed forks to PRIMPOL-dependent repriming, and its activity can become deleterious when checkpoint failure leaves nascent ends unprotected, causing fork collapse (PMID:32442397, PMID:40578346). Beyond replication, HLTF evicts the NER incision complex after dual incision to enable repair synthesis, removes Cas9 from cleaved DNA ends to permit DSB processing, and unfolds genomic G-quadruplex structures (PMID:35271816, PMID:38987539, PMID:39142279). It additionally functions as a histone H3K23 E3 ubiquitin ligase stimulated by H3K9me3, controlling chromatin accessibility (PMID:40680746), and as a transcription factor, regulating GATA1 in erythropoiesis and partnering with PIT-1 and the p11/annexin A2 complex in lactotrope and neuronal contexts (PMID:41521666, PMID:21507896, PMID:23415230). A germline HLTF E259K mutation that disrupts E2 binding and PCNA polyubiquitination is associated with familial MDS (PMID:30696947). HLTF abundance is tuned by the stabilizing deubiquitinase USP7 and by degradative E3 ligases including CHFR, β-TrCP and DTX2 (PMID:21845734, PMID:20388495, PMID:36822623, PMID:38163902), and HIV-1 Vpr hijacks the CRL4-DCAF1 ligase to degrade HLTF and counteract its restriction of HIV-1 (PMID:27114546, PMID:27335459, PMID:31019079).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2008 High

    Established HLTF as the human Rad5 ortholog by showing it polyubiquitinates PCNA, defining its core role in error-free postreplication repair.

    Evidence In vitro ubiquitin ligase assays, Co-IP with Rad6-Rad18 and Mms2-Ubc13, and rad5Δ yeast complementation

    PMID:18316726 PMID:18719106

    Open questions at the time
    • Did not define how HLTF is recruited to damaged forks
    • Did not address the function of the SWI/SNF ATPase domain
  2. 2009 Medium

    Showed HLTF carries intrinsic ATPase and ligase activities and physically associates with PTIP and RPA70, beginning to define its activity repertoire and partners.

    Evidence In vitro ATPase and ligase assays with multiple E2s plus pulldowns

    PMID:19723507

    Open questions at the time
    • Functional consequence of PTIP/RPA70 interactions not established
  3. 2009 High

    Demonstrated that the SWI/SNF motor drives replication fork reversal and fork restart, separating a translocase function from the ligase activity.

    Evidence In vitro fork reversal assays with ATPase-deficient mutants and chromosomal fiber analysis

    PMID:19948885

    Open questions at the time
    • Did not establish how the motor is targeted to forks
    • Physiological consequences of unregulated reversal unresolved
  4. 2011 High

    Defined a protein-clearance activity and a damage-specific division of labor with SHPRH, explaining how HLTF prepares stalled forks for bypass.

    Evidence In vitro protein displacement assays (RPA/PCNA/RFC) and siRNA/Co-IP analyses of TLS polymerase recruitment

    PMID:21396873 PMID:21795603

    Open questions at the time
    • Mechanism switching HLTF vs SHPRH after MMS not fully resolved
    • Structural basis of protein displacement unknown
  5. 2011 Medium

    Identified USP7 as a stabilizing deubiquitinase, the first node showing HLTF abundance is post-translationally tuned to control PCNA ubiquitination.

    Evidence Co-IP, deubiquitination and half-life assays with PCNA ubiquitination readout

    PMID:21845734

    Open questions at the time
    • Did not identify the counteracting degradative ligase
    • Single lab
  6. 2013 High

    Revealed HLTF can promote RAD51-independent D-loop formation, providing a template-switch route for gap repair independent of ATP hydrolysis.

    Evidence In vitro D-loop and primer extension assays with ATPase/ATP-binding mutants

    PMID:24198246

    Open questions at the time
    • In vivo relevance of D-loop activity not established
  7. 2015 High

    Solved how HLTF finds its substrate: the HIRAN OB-fold binds 3' ssDNA ends to recruit HLTF to stalled forks and direct translocase-driven fork reversal.

    Evidence Crystal structure of HIRAN-DNA, 3'-ssDNA binding and HIRAN-mutant fork reversal assays in vitro and in cells

    PMID:25858588 PMID:26051180 PMID:26350214

    Open questions at the time
    • Did not define how HIRAN coordinates with the motor at atomic level during translocation
  8. 2016 High

    Linked HLTF degradation to viral antagonism, showing HIV-1 Vpr exploits CRL4-DCAF1 to destroy HLTF independently of G2 arrest.

    Evidence Quantitative proteomics, proteasome-rescue Western blots, HIV-1 infection of primary T cells and macrophages

    PMID:27114546 PMID:27335459

    Open questions at the time
    • Antiviral function of HLTF itself not yet demonstrated at this stage
  9. 2016 Medium

    Provided a solution structure of the free HIRAN domain, revealing conformational heterogeneity at the DNA-binding site.

    Evidence Solution NMR structure determination

    PMID:27771863

    Open questions at the time
    • No functional mutagenesis in this work
    • Free-domain structure only
  10. 2017 High

    Detailed the molecular interface of Vpr-driven degradation, showing Vpr loads HLTF onto DCAF1 by engaging the HIRAN DNA-binding residues.

    Evidence In vitro reconstitution of Vpr-dependent HLTF polyubiquitination plus structure-guided mutagenesis

    PMID:29079575

    Open questions at the time
    • Single lab
    • Did not confirm HLTF antiviral phenotype
  11. 2018 High

    Dissected the regulated mechanics of PCNA polyubiquitination, showing HIRAN-recruited HLTF couples to RAD6-RAD18 monoubiquitination and is steered between en bloc and sequential modes by RFC/PCNA.

    Evidence Reconstituted in vitro ligase assays with HIRAN mutants and RFC/PCNA competition

    PMID:30335157

    Open questions at the time
    • Cellular relevance of the chain-elongation switch not directly tested
  12. 2019 Medium

    Confirmed HLTF restricts HIV-1 replication, establishing it as a genuine restriction factor antagonized by Vpr.

    Evidence Pairwise HIV-1 replication competition with Vpr separation-of-function mutants and HLTF knockdown

    PMID:31019079

    Open questions at the time
    • Molecular mechanism of restriction not defined
    • Single lab
  13. 2019 Medium

    Connected HLTF to human disease by showing a familial-MDS germline E259K mutation disrupts E2 binding and PCNA polyubiquitination, causing DSB accumulation.

    Evidence Co-IP of E259K with MMS2/UBC13, PCNA ubiquitination and γH2AX assays

    PMID:30696947

    Open questions at the time
    • Causality in MDS established only in cellular assays
    • Single family/lab
  14. 2020 High

    Established HLTF as the gatekeeper of fork remodeling choice, with its loss diverting forks to PRIMPOL repriming and altering DSB/survival outcomes.

    Evidence Electron microscopy of fork structures, PRIMPOL/REV1 epistasis, fiber assays and DSB quantification in HLTF KO/HIRAN mutants

    PMID:32442397

    Open questions at the time
    • Long-term genomic consequences of fork-reversal loss not defined
  15. 2020 High

    Defined the structural basis of HIRAN-initiated fork regression, showing it binds the 3'-OH and unwinds three nucleobases via Phe-142.

    Evidence Crystal structure of HIRAN-duplex DNA with Phe-142 mutagenesis

    PMID:31960921

    Open questions at the time
    • Coupling of HIRAN unwinding to the ATPase motor still inferred
  16. 2020 Medium

    Placed HLTF in the broader fork-protection network through interaction with PARP1 and co-recruitment with BRCA1/BARD1/RAD51, while defining its distinct dissociation behavior at collapsed forks.

    Evidence Co-IP, proximity ligation, DNA fiber analysis and immunofluorescence

    PMID:33281189

    Open questions at the time
    • Direct vs indirect HLTF-PARP1 interaction not fully resolved
    • Single lab
  17. 2020 Medium

    Showed APIM-mediated PCNA binding contributes to HLTF's TLS role and shapes UV mutation spectra, defining an additional PCNA-engagement mode.

    Evidence APIM mutant analysis, nuclear localization, SupF mutagenesis and PCNA binding assays

    PMID:31973093

    Open questions at the time
    • Relative contribution of APIM vs HIRAN to fork engagement unclear
  18. 2022 High

    Extended HLTF's translocase function into nucleotide excision repair, showing it evicts the incision complex to enable PCNA loading and repair synthesis.

    Evidence Reconstituted NER system, HIRAN mutant analysis, PCNA loading and cellular NER kinetics

    PMID:35271816

    Open questions at the time
    • In vivo contribution to NER efficiency across lesion types not quantified
  19. 2022 Medium

    Identified a conserved HLTF-MSH2 interaction linking HLTF to mismatch-repair machinery, distinguishing it from SHPRH-MLH1.

    Evidence Co-IP in human and yeast, bioinformatic conservation analysis and yeast two-hybrid

    PMID:35784486

    Open questions at the time
    • Functional role of HLTF-MSH2 in repair not established
  20. 2024 High

    Revealed a Cas9-eviction activity, showing HLTF removes Cas9 from cleaved ends via HIRAN/translocase to license DSB processing.

    Evidence Reconstituted Cas9 displacement assays, single-molecule assays, HIRAN mutants and cellular DSB repair readouts

    PMID:38987539

    Open questions at the time
    • Whether endogenous DNA-protein crosslinks are general substrates not defined
  21. 2024 High

    Demonstrated HLTF unfolds genomic G-quadruplexes via its translocase and restrains PrimPol repriming at stabilized G4s.

    Evidence In vitro G4 unfolding, G4 immunofluorescence/CUT&RUN in HLTF-KO cells, PrimPol epistasis and fiber assays

    PMID:39142279

    Open questions at the time
    • Genome-wide impact on G4-associated instability not fully mapped
  22. 2024 Medium

    Added DTX2 as a degradative ligase and supported a tumor-suppressor role for HLTF in glioma.

    Evidence Co-IP, in vitro ubiquitination and knockdown/overexpression in glioma cells and xenografts

    PMID:38163902

    Open questions at the time
    • Degradation signal/site on HLTF not mapped
    • Single lab
  23. 2023 Medium

    Identified β-TrCP as a degradative ligase coupling HLTF loss to p62/mTOR-driven HCC tumorigenesis.

    Evidence Co-IP, ubiquitination assays, signaling readouts and patient tissue correlation

    PMID:36822623

    Open questions at the time
    • Degron recognized by β-TrCP not defined
  24. 2025 Medium

    Defined a self-limiting axis where USP37 restrains HLTF accumulation at forks to prevent MRE11-dependent fork degradation.

    Evidence Co-IP, fiber assays, proximity ligation and USP37 KO + HLTF depletion epistasis

    PMID:40548939

    Open questions at the time
    • Whether USP37 acts catalytically or by sequestration unclear
  25. 2025 High

    Showed that excess HLTF activity is pathological in checkpoint-deficient cells, where it attacks unprotected nascent ends and drives irreversible fork collapse.

    Evidence HLTF KO in checkpoint-deficient cells, fiber assays, ssDNA accumulation and genetic epistasis

    PMID:40578346

    Open questions at the time
    • Mechanistic trigger distinguishing protective vs destructive HLTF action not fully defined
  26. 2025 High

    Established a chromatin-modifying function, identifying HLTF as an H3K23 E3 ligase stimulated by H3K9me3 that limits chromatin accessibility and tumor growth via its RING domain.

    Evidence In vitro histone ubiquitination with MS site identification, RING-mutant xenografts, ATAC-seq and CUT&Tag

    PMID:40680746

    Open questions at the time
    • Reader/effector of H3K23Ub not identified
  27. 2026 Medium

    Defined a transcriptional role in erythropoiesis, with HLTF and GATA1 forming a positive feedback loop that maintains erythroid chromatin accessibility.

    Evidence CUT&Tag, ATAC-seq, RNA-seq, Co-IP and GATA1-rescue of HLTF KO

    PMID:41521666

    Open questions at the time
    • Whether HLTF acts here as remodeler, ligase, or sequence-specific factor not resolved
  28. 2026 Medium

    Provided a mechanistic model for motor activation, showing fork binding and ATP induce HLTF dimerization required for unwinding and fork regression.

    Evidence Native mass spectrometry of HLTF-DNA complexes plus ATPase and fork regression assays

    PMID:42030070

    Open questions at the time
    • Dimer architecture and stoichiometry at forks not resolved structurally
    • Single lab/novel method

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HLTF's distinct activities—fork reversal, NER eviction, Cas9 removal, G4 unfolding, PCNA and H3K23 ubiquitination, and transcription—are selectively deployed and regulated in a context-specific manner remains unresolved.
  • No unifying model linking enzymatic activity choice to substrate context
  • Switch between protective and destructive fork action undefined
  • Structural basis for transcription-factor vs translocase modes unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 4 GO:0140110 transcription regulator activity 4 GO:0140657 ATP-dependent activity 4 GO:0003677 DNA binding 3 GO:0016874 ligase activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 3
Pathway
R-HSA-1643685 Disease 5 R-HSA-69306 DNA Replication 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-73894 DNA Repair 3 R-HSA-4839726 Chromatin organization 2
Partners
GATA1MMS2MSH2PARP1PCNARAD18UBC13USP7
Complex memberships
CRL4-DCAF1 (substrate of, via Vpr)p11/annexin A2 heterotetramer

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 HLTF functions as an E3 ubiquitin ligase that promotes Lys-63-linked polyubiquitination of PCNA at Lys-164, interacting physically with the Rad6-Rad18 and Mms2-Ubc13 ubiquitin-conjugating enzyme complexes to enable error-free postreplication repair of damaged DNA. In vitro ubiquitin ligase assay, co-immunoprecipitation, complementation of rad5Δ yeast strain, UV sensitivity assays Proceedings of the National Academy of Sciences of the United States of America High 18316726 18719106
2009 HLTF possesses ATP-dependent double-stranded DNA translocase activity that enables replication fork reversal (regression of model replication forks), and promotes restart of replication forks blocked at DNA lesions in vivo. In vitro fork reversal assay with ATPase-deficient mutants, chromosomal fiber analysis of dually labeled replication tracks Molecular and cellular biology High 19948885
2011 HLTF has an ATP hydrolysis-dependent protein remodeling activity that removes DNA-binding proteins (RPA, PCNA, RFC) from stalled replication forks, thereby clearing access for damage bypass factors. In vitro protein displacement assay with purified components, ATPase-deficient mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 21795603
2011 Following UV damage, HLTF enhances PCNA monoubiquitination and recruitment of TLS polymerase η while inhibiting SHPRH; following MMS damage, HLTF is degraded, allowing SHPRH to interact with Rad18 and polymerase κ. Thus HLTF and SHPRH act in a damage-specific manner to coordinate different branches of postreplication repair. siRNA knockdown, co-immunoprecipitation, mutagenesis assays, immunofluorescence of TLS polymerase recruitment Molecular cell High 21396873
2013 HLTF can form a D-loop (strand invasion) in a RAD51-independent manner without requiring ATP binding/hydrolysis; the 3' end of the invading strand in the D-loop can serve as a primer for DNA polymerase extension, providing a template-switch mechanism for gap repair. In vitro D-loop formation assay with purified proteins, ATPase-deficient mutants, primer extension assay Nucleic acids research High 24198246
2015 The HIRAN domain of HLTF is an OB-fold structure that specifically binds 3' ssDNA ends; this interaction recruits HLTF to stalled replication forks and drives fork reversal activity. HIRAN domain mutations abolish fork reversal in vitro and replication fork slowing in cells. Crystal structure of HIRAN-DNA complex, biochemical 3'-ssDNA binding assays, HIRAN mutant fork reversal assays in vitro, replication fork progression assays in cells Molecular cell High 25858588 26051180
2015 HIRAN domain mutant HLTF retains ubiquitin ligase, ATPase, and dsDNA translocase activities but is specifically impaired in binding model replication fork structures, demonstrating that the HIRAN domain recruits HLTF to stalled forks and provides directional guidance for the translocase motor during fork reversal. HIRAN domain mutagenesis, in vitro fork binding and reversal assays, ATPase assays, ubiquitin ligase assays, cellular postreplication repair gap-filling assay Nucleic acids research High 26350214
2016 HIV-1 Vpr subverts the DCAF1 adaptor of the CRL4A E3 ubiquitin ligase to trigger proteasomal degradation of HLTF in T cells and macrophages; this degradation occurs independently of Vpr-mediated G2 arrest. Quantitative proteomic screen, Western blot degradation assay, proteasome inhibitor rescue, HIV-1 infection experiments in primary T cells and macrophages Proceedings of the National Academy of Sciences of the United States of America High 27114546 27335459
2017 HIV-1 Vpr directly loads HLTF onto the WD40 domain of DCAF1 within the CRL4 E3 ubiquitin ligase, mediating HLTF polyubiquitination. Vpr interacts with DNA-binding residues in HLTF's HIRAN domain and a second region connecting HIRAN to the ATPase/helicase domains. In vitro reconstitution of Vpr-dependent HLTF polyubiquitination, mutational analysis of HIRAN domain interaction interface The Journal of biological chemistry High 29079575
2019 HLTF restricts HIV-1 replication in activated primary CD4+ T cells; this restriction is antagonized by HIV-1 Vpr via CRL4-DCAF1-dependent degradation of HLTF. Pairwise HIV-1 replication competition assay, HLTF knockdown, Vpr separation-of-function mutants Proceedings of the National Academy of Sciences of the United States of America Medium 31019079
2011 USP7 (ubiquitin-specific protease 7) interacts with HLTF and stabilizes it after genotoxic stress by deubiquitination, prolonging HLTF half-life and thereby increasing PCNA polyubiquitination. Co-immunoprecipitation, ubiquitination assay, half-life/stability assay, siRNA knockdown with PCNA ubiquitination readout Journal of cellular biochemistry Medium 21845734
2010 CHFR E3 ubiquitin ligase binds to and ubiquitinates HLTF, leading to its proteasomal degradation; HLTF modulates basal expression of PAI-1, and CHFR-mediated HLTF degradation reduces PAI-1 expression and inhibits cell migration. Co-immunoprecipitation, in vitro ubiquitination assay, cell migration assay, PAI-1 expression analysis Biochemical and biophysical research communications Medium 20388495
2009 HLTF has intrinsic ATPase activity and E3 ubiquitin ligase activity with a range of E2 ubiquitin-conjugating enzymes in vitro. PTIP and RPA70 were identified as HLTF-interacting proteins. In vitro ATPase assay, in vitro ubiquitin ligase assay, co-immunoprecipitation/pulldown Biochemical and biophysical research communications Medium 19723507
2020 In HLTF-deficient cells, replication forks fail to undergo reversal following replication stress and instead rely on PRIMPOL for repriming and unrestrained replication. In HLTF-HIRAN mutant cells, unrestrained replication depends on REV1 (TLS). HLTF-deficient cells show reduced DSB formation and increased survival under replication stress. HLTF knockout/HIRAN mutant cells, electron microscopy of fork structures, PRIMPOL and REV1 epistasis analysis, DNA fiber assay, DSB quantification Molecular cell High 32442397
2022 HLTF is recruited to the NER incision complex in a dual-incision-dependent manner via its HIRAN domain binding to 3'-OH single-stranded DNA ends; HLTF's translocase motor then promotes dissociation of the incision complex together with the incised oligonucleotide, enabling efficient PCNA loading and repair synthesis. In vitro NER reconstitution, HLTF recruitment assay, HIRAN domain mutant analysis, PCNA loading assay, cellular NER kinetics Molecular cell High 35271816
2016 Solution NMR structure of the human HLTF HIRAN domain reveals an OB-like fold; the free domain exhibits conformational heterogeneity at its DNA-binding site. Sequence comparison suggests SHPRH N-terminus contains an uncharacterized structured module with weak HIRAN similarity. Solution NMR structure determination Journal of biomolecular NMR Medium 27771863
2018 HLTF ligase activity is stimulated by double-stranded DNA via HIRAN domain-dependent recruitment to stalled primer ends; RFC and PCNA at primer ends suppress en bloc PCNA polyubiquitination, redirecting to sequential chain elongation. When PCNA is monoubiquitinated by RAD6-RAD18 in the presence of HLTF, the ubiquitin is immediately polyubiquitinated by HLTF (coupled reaction). In vitro ubiquitin ligase assay with reconstituted components, HIRAN mutant analysis, RFC/PCNA competition assay Nucleic acids research High 30335157
2020 HLTF and SHPRH contain functional APIM (AlkB homologue 2 PCNA-interacting motif) sequences that mediate direct binding to PCNA; HLTF's role in TLS in overexpressing cells and nuclear localization of SHPRH depend on APIM-PCNA interaction. APIM mutation in HLTF alters mutation spectra, decreasing C-to-T transitions after UV. APIM mutant analysis, nuclear localization assay, mutagenesis (SupF) assay, PCNA binding assay International journal of molecular sciences Medium 31973093
2013 In pituitary lactotrope cells, HLTF (SMARCA3) binds the prolactin promoter E-box and interacts with the pituitary-specific factor PIT-1; NONO and SFPQ are HLTF-associated proteins identified by mass spectrometry that bind rhythmically to the prolactin promoter and regulate circadian prolactin transcription. NONO/SFPQ overexpression reduces Prl promoter activity and disrupts circadian pattern. Chromatin immunoprecipitation, mass spectrometry identification of HLTF-associated proteins, co-immunoprecipitation, promoter reporter assays, overexpression studies FASEB journal Medium 21507896
2013 SMARCA3/HLTF is a target of the p11/annexin A2 heterotetrameric complex; crystal structure shows SMARCA3 peptide binds a hydrophobic pocket in the heterotetramer; complex formation increases SMARCA3 DNA-binding affinity and its localization to the nuclear matrix fraction. SSRI-induced neurogenesis and behavioral responses are abolished by constitutive SMARCA3 knockout. Crystal structure of SMARCA3 peptide-heterotetramer complex, DNA-binding affinity assay, nuclear fractionation, SMARCA3 knockout behavioral/neurogenesis assays Cell High 23415230
2021 The p11/SMARCA3 complex represses Neurensin-2 transcription in hippocampal parvalbumin-expressing interneurons after chronic SSRI treatment; SMARCA3 accumulates in the cell nucleus upon SSRI treatment and regulates AMPA-receptor signaling in these interneurons. Cell-type-specific knockout, nuclear fractionation, gene expression analysis, behavioral assays, electrophysiology Molecular psychiatry Medium 33723417
2019 A germline HLTF E259K mutation found in familial MDS reduces HLTF binding to ubiquitin-conjugating enzymes MMS2 and UBC13, resulting in impaired PCNA polyubiquitination and accumulation of DNA double-strand breaks. Co-immunoprecipitation of E259K mutant with E2 enzymes, PCNA ubiquitination assay, γH2AX immunofluorescence Leukemia Medium 30696947
2020 HLTF interacts with PARP1; depletion of HLTF and PARP1 together increases chromosome breaks and reduces replication track length after MMS treatment. HLTF and PARP1 are initially recruited to damaged forks together with BRCA1/BARD1/RAD51, but HLTF and PCNA dissociate from collapsed forks while PARP1 and BRCA1/BARD1/RAD51 accumulate further. Co-immunoprecipitation, proximity ligation assay, DNA fiber analysis, immunofluorescence Oncogenesis Medium 33281189
2020 Crystal structure of the HLTF HIRAN domain bound to duplex DNA reveals that HIRAN binds the 3'-hydroxyl group and unexpectedly unwinds three nucleobases; Phe-142 is required for dsDNA binding and strand separation, suggesting direct involvement of HIRAN in initiating fork regression by separating daughter strand from parental template. Crystal structure of HIRAN-duplex DNA complex, mutational analysis of Phe-142 Journal of biochemistry High 31960921
2022 HLTF interacts with MSH2 (a component of MutS heterodimers); this interaction is conserved from yeast Rad5/Msh2 to human HLTF/MSH2. SHPRH (not HLTF) interacts with MLH1. Co-immunoprecipitation, bioinformatic identification of conserved interaction, yeast two-hybrid Frontiers in cell and developmental biology Medium 35784486
2024 HLTF directly removes Cas9 from broken DNA ends via its HIRAN domain and translocase activity, enabling DSB processing by MRE11-dependent resection or NHEJ. HLTF activity requires binding the 3'-end generated by cleavage of the non-target strand (RuvC domain); HLTF removes H840A but not D10A Cas9 nickase. In vitro Cas9 displacement assay (reconstitution), single-molecule assay, HIRAN domain mutant analysis, cellular DSB repair assay Nature communications High 38987539
2024 HLTF is enriched at G4 loci in the human genome, can directly unfold G4 structures in vitro using its ATP-dependent translocase activity, and suppresses G4 accumulation throughout the cell cycle. HLTF also restrains PrimPol-dependent repriming when G4s are stabilized, preventing unrestrained DNA synthesis. In vitro G4 unfolding assay, G4 immunofluorescence/CUT&RUN in HLTF-KO cells, PrimPol epistasis, DNA fiber assay Molecular cell High 39142279
2023 β-TrCP mediates ubiquitination and proteasomal degradation of HLTF in hepatocellular carcinoma; HLTF knockdown enhances p62 transcriptional activity and mTOR activation, promoting HCC tumorigenesis. Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression with mTOR signaling readouts, patient tissue correlation Journal of molecular cell biology Medium 36822623
2025 When the DNA replication checkpoint is non-functional, excess DNA synthesis sequesters PCNA and RFC, leaving nascent DNA ends unprotected; HLTF attacks these unprotected ends, causing irreversible replication fork collapse and ssDNA hyperaccumulation. Loss of HLTF suppresses fork collapse and cell lethality in checkpoint-deficient cells. HLTF knockout in checkpoint-deficient human cells, DNA fiber assay, ssDNA accumulation assay, genetic epistasis Molecular cell High 40578346
2025 USP37 interacts with HLTF and limits HLTF accumulation at replication forks, thereby preventing MRE11-dependent fork degradation upon replication stress. Depletion of HLTF reverses replication-associated damage in USP37 knockout cells. Co-immunoprecipitation, DNA fiber assay, proximity ligation assay, genetic epistasis (USP37 KO + HLTF depletion) Nucleic acids research Medium 40548939
2025 SMARCA3/HLTF acts as an E3 ubiquitin ligase that targets histone H3 at lysine 23 (H3K23Ub); this activity is stimulated by the H3K9me3 mark. Loss of SMARCA3 reduces both H3K23Ub and H3K9me3, increasing chromatin accessibility at promoters and enhancers, and suppression of tumor growth requires the intact RING domain. In vitro histone ubiquitination assay, mass spectrometry identification of H3K23Ub, RING domain mutant in xenograft model, ATAC-seq, CUT&Tag Molecular cell High 40680746
2026 HLTF directly binds the GATA1 promoter to enhance GATA1 transcription; HLTF physically interacts with GATA1 protein and co-occupies erythroid regulatory regions, facilitating GATA1 genomic binding and maintaining chromatin accessibility. GATA1 also transcriptionally activates HLTF, forming a positive feedback loop. ChIP-seq (CUT&Tag), ATAC-seq, RNA-seq, co-immunoprecipitation, HLTF KO rescue by GATA1 overexpression Nucleic acids research Medium 41521666
2026 HLTF exists as an inactive monomer with low ATP accessibility but retains DNA fork binding activity; in the presence of a DNA fork, monomeric HLTF forms a hetero protein-DNA complex that enhances ATP accessibility via allosteric modulation. ATP induces HLTF dimerization, which is critical for DNA unwinding and fork regression. Native mass spectrometry of HLTF-DNA complexes, ATPase assay, DNA fork regression assay Journal of the American Chemical Society Medium 42030070
2021 In fission yeast, Rad8/HLTF facilitates Rad52-dependent gross chromosomal rearrangements (GCRs) through ubiquitination of PCNA at lysine 107 (not the canonical K164); Rad8 HIRAN and RING finger mutations reduce GCRs, indicating both 3'-DNA end binding and ubiquitin ligase activity are required. Genetic epistasis in rad51Δ fission yeast, HIRAN and RING mutant analysis, PCNA K107R mutation, GCR frequency assay PLoS genetics Medium 34292936
2024 DTX2 E3 ubiquitin ligase interacts with HLTF and promotes its ubiquitination and degradation; HLTF acts as a tumor suppressor in glioma, inhibiting proliferation and migration. Co-immunoprecipitation, in vitro ubiquitination assay, knockdown/overexpression in glioma cells and xenografts Biology direct Medium 38163902
2025 LINC01088 lncRNA acts as a scaffold to bridge HLTF and USP7, enhancing HLTF-USP7 interaction and preventing ubiquitin-mediated degradation of HLTF. Stabilized HLTF transcriptionally upregulates SLC7A11, inhibiting ferroptosis in glioblastoma. RNA pulldown, co-immunoprecipitation, RNA immunoprecipitation, ChIP assay, rescue experiments with HLTF modulation Clinical and translational medicine Medium 40000422
2023 HLTF interacts with SRSF1 and contributes to SRSF1 protein stability, activating the ERK/MAPK signaling pathway to promote HCC proliferation and metastasis. Co-immunoprecipitation, SRSF1 stability assay, ERK/MAPK pathway readout, knockdown/overexpression in HCC cells and xenografts Oncogenesis Medium 36670110
2025 HLTF is identified as a transcriptional regulator of CD137L, controlling its expression through phosphorylation of serine at position 398 of HLTF. Multi-omics data integration, phospho-mutant analysis, CD137L promoter regulation assays Nature communications Low 41006211
2024 HLTF transcriptionally activates SERPINE1 (PAI-1) in cervical carcinoma cells; this was validated by ChIP demonstrating HLTF binding to the SERPINE1 promoter. Chromatin immunoprecipitation, transcriptome sequencing, knockdown/overexpression rescue experiments Gynecologic and obstetric investigation Low 39348822
2003 Progesterone regulates RUSH/SMARCA3 transcription via a progesterone receptor half-site/overlapping Y-box element in the promoter; Sp1 sites repress basal transcription. The RING finger domain of RUSH mediates protein-protein interactions with Egr-1 and c-Rel. Truncation/mutation analysis in transfection assays, gel shift assays, chromatin immunoprecipitation, primer extension The Journal of biological chemistry Medium 12890680
2008 RUSH/SMARCA3 bound to a distal site (-616/-611) loops the intervening DNA to interact with Egr-1 and c-Rel at the proximal promoter in a progesterone-dependent manner; this DNA looping mediates repression by c-Rel and is dependent on the RING finger protein-interaction domain of RUSH. Chromosome Conformation Capture (3C) assay, fluorescence microscopy, GST pulldown, ChIP, supershift assays, transient transfection with mutant constructs Molecular endocrinology Medium 18174357

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks. Proceedings of the National Academy of Sciences of the United States of America 238 18719106
2008 Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination. Proceedings of the National Academy of Sciences of the United States of America 207 18316726
2015 HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal. Molecular cell 175 26051180
2020 HLTF Promotes Fork Reversal, Limiting Replication Stress Resistance and Preventing Multiple Mechanisms of Unrestrained DNA Synthesis. Molecular cell 160 32442397
2009 Role of double-stranded DNA translocase activity of human HLTF in replication of damaged DNA. Molecular and cellular biology 160 19948885
2010 Role of yeast Rad5 and its human orthologs, HLTF and SHPRH in DNA damage tolerance. DNA repair 154 20096653
2011 SHPRH and HLTF act in a damage-specific manner to coordinate different forms of postreplication repair and prevent mutagenesis. Molecular cell 152 21396873
2002 HLTF gene silencing in human colon cancer. Proceedings of the National Academy of Sciences of the United States of America 139 11904375
2017 Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability. Critical reviews in biochemistry and molecular biology 124 28954549
2013 SMARCA3, a chromatin-remodeling factor, is required for p11-dependent antidepressant action. Cell 92 23415230
2016 HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages. Proceedings of the National Academy of Sciences of the United States of America 76 27114546
2011 Coordinated protein and DNA remodeling by human HLTF on stalled replication fork. Proceedings of the National Academy of Sciences of the United States of America 70 21795603
2016 HIV-1 and HIV-2 exhibit divergent interactions with HLTF and UNG2 DNA repair proteins. Proceedings of the National Academy of Sciences of the United States of America 66 27335459
2015 Structure of a Novel DNA-binding Domain of Helicase-like Transcription Factor (HLTF) and Its Functional Implication in DNA Damage Tolerance. The Journal of biological chemistry 63 25858588
2015 Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling. Nucleic acids research 63 26350214
2018 Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress. Cell reports 62 30232006
2011 HLTF and SHPRH are not essential for PCNA polyubiquitination, survival and somatic hypermutation: existence of an alternative E3 ligase. DNA repair 54 21269891
2013 Strand invasion by HLTF as a mechanism for template switch in fork rescue. Nucleic acids research 53 24198246
2003 Methylation pattern of HLTF gene in digestive tract cancers. International journal of cancer 46 12584739
2012 Loss of HLTF function promotes intestinal carcinogenesis. Molecular cancer 42 22452792
2016 The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor? Cellular and molecular life sciences : CMLS 38 26472339
2022 Active DNA damage eviction by HLTF stimulates nucleotide excision repair. Molecular cell 36 35271816
2003 DNA hypermethylation and histone hypoacetylation of the HLTF gene are associated with reduced expression in gastric carcinoma. Cancer science 35 12901794
2019 HIV-1 Vpr counteracts HLTF-mediated restriction of HIV-1 infection in T cells. Proceedings of the National Academy of Sciences of the United States of America 34 31019079
2009 Biochemical characterisation of the SWI/SNF family member HLTF. Biochemical and biophysical research communications 34 19723507
2011 USP7 regulates the stability and function of HLTF through deubiquitination. Journal of cellular biochemistry 32 21845734
2011 Chromatin remodeling as a mechanism for circadian prolactin transcription: rhythmic NONO and SFPQ recruitment to HLTF. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 31 21507896
2017 ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells. Autophagy 29 28981387
2018 Regulation of HLTF-mediated PCNA polyubiquitination by RFC and PCNA monoubiquitination levels determines choice of damage tolerance pathway. Nucleic acids research 26 30335157
2013 Role of helicase-like transcription factor (hltf) in the G2/m transition and apoptosis in brain. PloS one 26 23826137
2024 HLTF disrupts Cas9-DNA post-cleavage complexes to allow DNA break processing. Nature communications 24 38987539
2018 HLTF suppresses the migration and invasion of colorectal cancer cells via TGF‑β/SMAD signaling in vitro. International journal of oncology 24 30320371
2016 SHORT HYPOCOTYL1 Encodes a SMARCA3-Like Chromatin Remodeling Factor Regulating Elongation. Plant physiology 24 27559036
2013 Helicase-like transcription factor (Hltf) regulates G2/M transition, Wt1/Gata4/Hif-1a cardiac transcription networks, and collagen biogenesis. PloS one 24 24278285
2003 An Sp1-NF-Y/progesterone receptor DNA binding-dependent mechanism regulates progesterone-induced transcriptional activation of the rabbit RUSH/SMARCA3 gene. The Journal of biological chemistry 24 12890680
2017 HIV-1 Vpr protein directly loads helicase-like transcription factor (HLTF) onto the CRL4-DCAF1 E3 ubiquitin ligase. The Journal of biological chemistry 23 29079575
2006 Early expression of the Helicase-Like Transcription Factor (HLTF/SMARCA3) in an experimental model of estrogen-induced renal carcinogenesis. Molecular cancer 23 16762066
2020 Helicase-Like Transcription Factor HLTF and E3 Ubiquitin Ligase SHPRH Confer DNA Damage Tolerance through Direct Interactions with Proliferating Cell Nuclear Antigen (PCNA). International journal of molecular sciences 20 31973093
2024 HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability. Molecular cell 19 39142279
2008 Progesterone-dependent deoxyribonucleic acid looping between RUSH/SMARCA3 and Egr-1 mediates repression by c-Rel. Molecular endocrinology (Baltimore, Md.) 18 18174357
2016 Solution NMR structure of the HLTF HIRAN domain: a conserved module in SWI2/SNF2 DNA damage tolerance proteins. Journal of biomolecular NMR 17 27771863
2025 LINC01088 prevents ferroptosis in glioblastoma by enhancing SLC7A11 via HLTF/USP7 axis. Clinical and translational medicine 15 40000422
2025 The DNA replication checkpoint prevents PCNA/RFC depletion to protect forks from HLTF-induced collapse in human cells. Molecular cell 15 40578346
2011 Aberrant methylation of the CpG island of HLTF gene in gastric cardia adenocarcinoma and dysplasia. Clinical biochemistry 15 21531217
2010 CHFR functions as a ubiquitin ligase for HLTF to regulate its stability and functions. Biochemical and biophysical research communications 15 20388495
2019 Post-replication repair: Rad5/HLTF regulation, activity on undamaged templates, and relationship to cancer. Critical reviews in biochemistry and molecular biology 14 31429594
2004 Prolactin signals through RUSH/SMARCA3 in the absence of a physical association with Stat5a. Biology of reproduction 14 15306550
2020 The HLTF-PARP1 interaction in the progression and stability of damaged replication forks caused by methyl methanesulfonate. Oncogenesis 13 33281189
2019 A germline HLTF mutation in familial MDS induces DNA damage accumulation through impaired PCNA polyubiquitination. Leukemia 13 30696947
2021 Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants. Molecular psychiatry 12 33723417
2019 Helicase-like transcription factor (Hltf) gene-deletion promotes oxidative phosphorylation (OXPHOS) in colorectal tumors of AOM/DSS-treated mice. PloS one 12 31461471
2023 HLTF promotes hepatocellular carcinoma progression by enhancing SRSF1 stability and activating ERK/MAPK pathway. Oncogenesis 11 36670110
2020 The Human RAD5 Homologs, HLTF and SHPRH, Have Separate Functions in DNA Damage Tolerance Dependent on The DNA Lesion Type. Biomolecules 11 32192191
2018 Alternative splicing of helicase-like transcription factor (Hltf): Intron retention-dependent activation of immune tolerance at the feto-maternal interface. PloS one 11 29975766
2020 Structure of HIRAN domain of human HLTF bound to duplex DNA provides structural basis for DNA unwinding to initiate replication fork regression. Journal of biochemistry 10 31960921
2011 DNA damage discrimination at stalled replication forks by the Rad5 homologs HLTF and SHPRH. Molecular cell 10 21504827
2022 Rad5 and Its Human Homologs, HLTF and SHPRH, Are Novel Interactors of Mismatch Repair. Frontiers in cell and developmental biology 9 35784486
2021 Fission yeast Rad8/HLTF facilitates Rad52-dependent chromosomal rearrangements through PCNA lysine 107 ubiquitination. PLoS genetics 9 34292936
2010 [Hypermethylation of the CDH1, SEPT9, HLTF and ALX4 genes and their diagnostic significance in colorectal cancer]. Voprosy onkologii 9 20552891
2023 Degradation of helicase-like transcription factor (HLTF) by β-TrCP promotes hepatocarcinogenesis via activation of the p62/mTOR axis. Journal of molecular cell biology 8 36822623
2025 The SWI/SNF-related protein SMARCA3 is a histone H3K23 ubiquitin ligase that regulates H3K9me3 in cancer. Molecular cell 7 40680746
2023 Helicase-like transcription factor (HLTF)-deleted CDX/TME model of colorectal cancer increased transcription of oxidative phosphorylation genes and diverted glycolysis to boost S-glutathionylation in lymphatic intravascular metastatic niches. PloS one 6 37682902
2020 Structure of the HLTF HIRAN domain and its functional implications in regression of a stalled replication fork. Acta crystallographica. Section D, Structural biology 6 32744255
2008 Progesterone regulation of RUSH/SMARCA3/HLTF includes DNA looping. Biochemical Society transactions 6 18631131
2024 DTX2 promotes glioma development via regulation of HLTF. Biology direct 4 38163902
2023 HLTF Prevents G4 Accumulation and Promotes G4-induced Fork Slowing to Maintain Genome Stability. bioRxiv : the preprint server for biology 4 37961428
2022 DNA Sequence Specificity Reveals a Role of the HLTF HIRAN Domain in the Recognition of Trinucleotide Repeats. Biochemistry 4 35608245
2023 Helicase-like transcription factor (Hltf)-deletion activates Hmgb1-Rage axis and granzyme A-mediated killing of pancreatic β cells resulting in neonatal lethality. PloS one 3 37624843
2015 Crystallographic study of a novel DNA-binding domain of human HLTF involved in the template-switching pathway to avoid the replication arrest caused by DNA damage. Acta crystallographica. Section F, Structural biology communications 3 26057792
2025 USP37 counteracts HLTF to protect damaged replication forks and promote survival of BRCA1-deficient cells and PARP inhibitor resistance. Nucleic acids research 2 40548939
2025 CD137L promotes immune surveillance in melanoma via HLTF regulation. Nature communications 1 41006211
2024 Computational study of the HLTF ATPase remodeling domain suggests its activity on dsDNA and implications in damage tolerance. Journal of structural biology 1 39491691
2024 CBX3 Downregulates HLTF to Activate PI3K/AKT Signaling Promoting Cholangiocarcinoma. Advanced biology 1 39601498
2026 HLTF cooperates with GATA1 to activate transcriptional programs and chromatin remodeling during erythroid development. Nucleic acids research 0 41521666
2026 Elucidating HLTF-Mediated DNA Fork Remodeling via Native Mass Spectrometry. Journal of the American Chemical Society 0 42030070
2025 HLTF Promotes the Proliferation of Osteosarcoma Cells and Cisplatin Resistance. Anti-cancer agents in medicinal chemistry 0 40129144
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
2024 HLTF/SERPINE1 Axis Plays a Crucial Pro-Oncogenic Role in the Progression from Cervical Precancerous Lesions to Cervical Carcinoma in vitro. Gynecologic and obstetric investigation 0 39348822
2008 Mutation screening of the SMARCA3 gene in Swedish colorectal cancer patients. Molecular medicine reports 0 21479407

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