Affinage

HLTF

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

Length
1009 aa
Mass
113.9 kDa
Annotated
2026-04-28
79 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HLTF is a SWI/SNF-family ATPase that couples E3 ubiquitin ligase activity with dsDNA translocase and chromatin-remodeling functions to maintain genome integrity at stalled replication forks, resolve non-B-form DNA structures, and regulate chromatin state. As the functional human orthologue of yeast Rad5, HLTF catalyzes Lys-63-linked polyubiquitination of PCNA via the Mms2–Ubc13 E2 complex to promote error-free damage tolerance (PMID:18316726, PMID:18719106), while its ATP-dependent dsDNA translocase drives replication fork reversal, clearance of fork-bound proteins (RPA, PCNA, RFC), eviction of NER incision complexes, unfolding of G-quadruplex structures, and removal of Cas9 from cleaved DNA ends — activities directed by a HIRAN OB-fold domain that recognizes 3′-OH DNA termini and promotes strand separation (PMID:19948885, PMID:21795603, PMID:26051180, PMID:35271816, PMID:39142279, PMID:38987539). HLTF also functions as an H3K23 E3 ubiquitin ligase stimulated by H3K9me3, maintaining repressive chromatin at promoters and enhancers, and participates in erythroid gene regulation through a positive-feedback loop with GATA1 (PMID:40680746, PMID:41521666). A germline HLTF E259K mutation that impairs PCNA polyubiquitination has been identified in familial myelodysplastic syndrome (PMID:30696947).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2008 High

    Establishing HLTF as the functional human Rad5 orthologue resolved how Lys-63-linked PCNA polyubiquitination is catalyzed in mammalian cells, linking HLTF's RING domain E3 ligase activity with Mms2–Ubc13 and Rad6–Rad18 to the error-free branch of post-replication repair.

    Evidence In vitro ubiquitin ligase reconstitution, yeast rad5Δ complementation, Co-IP, and chromosomal analysis of Hltf-deficient MEFs

    PMID:18316726 PMID:18719106

    Open questions at the time
    • Structural basis for RING-E2 interaction not determined
    • Relative contributions of HLTF versus SHPRH to PCNA polyubiquitination in vivo not quantified
  2. 2009 High

    Demonstrating that HLTF possesses ATP-dependent dsDNA translocase activity capable of reversing model replication forks in vitro established a second, mechanistically distinct function beyond ubiquitin ligation — replication fork remodeling.

    Evidence In vitro fork reversal assay and ATPase assay combined with DNA fiber analysis of labeled chromosomal fibers in vivo

    PMID:19948885

    Open questions at the time
    • Structural basis of translocase activity unknown
    • How fork reversal and PCNA polyubiquitination are coordinated on the same substrate unclear
  3. 2011 High

    Discovery that HLTF uses ATP hydrolysis to displace RPA, PCNA, and RFC from fork substrates revealed a protein-remodeling function that clears the path for damage bypass or fork regression, explaining how HLTF gains access to stalled fork DNA.

    Evidence In vitro protein displacement assay on reconstituted fork substrates

    PMID:21795603

    Open questions at the time
    • Order of protein removal events in vivo not established
    • Whether remodeling and ubiquitin ligase activities occur simultaneously or sequentially unknown
  4. 2011 High

    Identification of damage-type-specific regulation — HLTF stabilization after UV versus degradation after MMS — and USP7-mediated deubiquitination revealed that HLTF protein levels are dynamically tuned to control which PRR branch operates.

    Evidence siRNA knockdown, Co-IP, PCNA ubiquitination assays, damage sensitivity assays; USP7 deubiquitination and half-life measurements

    PMID:21396873 PMID:21845734

    Open questions at the time
    • E3 ligase(s) responsible for damage-induced HLTF degradation after MMS not yet identified at this point
    • Quantitative relationship between HLTF levels and PRR pathway choice not modeled
  5. 2013 High

    Showing that HLTF catalyzes RAD51-independent D-loop formation with extendable 3′ ends expanded its mechanistic repertoire to include strand invasion for template switching, independent of canonical homologous recombination.

    Evidence In vitro D-loop formation and DNA polymerase extension assays

    PMID:24198246

    Open questions at the time
    • Physiological relevance of RAD51-independent D-loops not demonstrated in cells
    • Whether this activity contributes to template switching in vivo unresolved
  6. 2013 High

    The crystal structure of HLTF/SMARCA3 peptide bound to p11/annexin A2 heterotetramer, together with SMARCA3 knockout abolishing SSRI-induced neurogenesis and behavior, established a neuronal chromatin-regulatory role for HLTF distinct from its DNA repair functions.

    Evidence Crystal structure, DNA-binding affinity assays, nuclear fractionation, constitutive KO behavioral assays

    PMID:23415230

    Open questions at the time
    • Target genes regulated by SMARCA3 in neurons incompletely characterized
    • Whether DNA repair and neuronal chromatin functions are mutually exclusive unknown
  7. 2015 High

    Crystal structures of the HIRAN domain bound to 3′-OH ssDNA and duplex DNA, combined with functional mutagenesis, identified HIRAN as an OB-fold 3′-DNA-end sensor that recruits HLTF to stalled forks and provides directional guidance for fork reversal, resolving how HLTF recognizes its substrate.

    Evidence X-ray crystallography of HIRAN–DNA complexes, solution NMR of free HIRAN, fluorescence polarization, HIRAN mutant cellular gap-filling and fiber assays

    PMID:25858588 PMID:26051180 PMID:26350214

    Open questions at the time
    • Full-length HLTF structure and HIRAN–motor domain communication not resolved
    • Structural basis for coupling HIRAN recognition to translocase engagement unknown
  8. 2016 High

    Discovery that HIV-1 Vpr hijacks the CRL4-DCAF1 E3 ligase to target HLTF for proteasomal degradation revealed a viral strategy to neutralize DNA damage tolerance, and subsequent work showed this confers a replication advantage to HIV-1 in primary CD4+ T cells.

    Evidence Quantitative proteomics, Co-IP, proteasome inhibitor experiments, in vitro reconstituted ubiquitination, Vpr mutant competition assays in primary T cells

    PMID:27114546 PMID:29079575 PMID:31019079

    Open questions at the time
    • Precise mechanism by which HLTF restriction limits HIV-1 replication not defined
    • Whether HLTF degradation alone or combined loss of multiple Vpr targets drives the phenotype not fully separated
  9. 2018 High

    Reconstitution of DNA-stimulated PCNA polyubiquitination showed that HIRAN-mediated recruitment to primer ends activates the ligase, while RFC/PCNA at those ends redirect chain assembly from en bloc to sequential elongation, revealing allosteric regulation of the ubiquitin transfer mechanism.

    Evidence In vitro PCNA ubiquitination reconstitution with defined DNA substrates and protein combinations

    PMID:30335157

    Open questions at the time
    • How chain topology (en bloc vs. sequential) influences downstream pathway choice in vivo unknown
    • Structural basis of RFC/PCNA-mediated redirection not resolved
  10. 2018 High

    iPOND-based identification of HLTF accumulation at forks in FANCJ-deficient cells, and reciprocal genetic epistasis, established that HLTF and FANCJ counterbalance each other to prevent excessive fork remodeling and degradation.

    Evidence iPOND proteomics, DNA fiber analysis, FANCJ/HLTF double KO cells

    PMID:30232006

    Open questions at the time
    • Direct physical interaction between HLTF and FANCJ not demonstrated
    • Mechanism by which FANCJ limits HLTF fork access unknown
  11. 2020 High

    Electron microscopy of replication intermediates in HLTF-deficient and HIRAN-mutant cells proved HLTF is the major fork reversal enzyme in vivo and showed that its loss reroutes tolerance through PRIMPOL repriming or REV1-dependent TLS, depending on whether the HIRAN domain is absent or mutated.

    Evidence EM-based fork structure analysis, DNA fiber assays, genetic epistasis with PRIMPOL and REV1, HIRAN mutant cell lines

    PMID:32442397

    Open questions at the time
    • Why HIRAN mutation channels through REV1 rather than PRIMPOL not mechanistically explained
    • Contribution of other fork reversal factors (SMARCAL1, ZRANB3) in HLTF-deficient background not fully delineated
  12. 2020 High

    A crystal structure of HIRAN bound to duplex DNA revealed that Phe-142-mediated unwinding of three base pairs at the 3′ end provides the strand-separating step that initiates fork regression, establishing HIRAN as an active strand separator rather than a passive recognition module.

    Evidence X-ray crystallography of HIRAN–duplex DNA complex, mutational analysis

    PMID:31960921

    Open questions at the time
    • How unwinding by HIRAN is handed off to the SWI/SNF motor for processive translocation not known
  13. 2022 High

    Reconstitution of HLTF function in NER demonstrated that HLTF is recruited to dual-incision intermediates via HIRAN binding to the 3′-OH ssDNA end and uses its translocase to evict the incised oligonucleotide and disassemble the repair complex, expanding HLTF's role beyond replication-associated repair.

    Evidence In vitro NER reconstitution with HLTF, HIRAN mutant analysis, PCNA loading assays

    PMID:35271816

    Open questions at the time
    • In vivo contribution of HLTF to NER not quantified
    • Whether HLTF collaborates with other post-incision factors unknown
  14. 2024 High

    Demonstration that HLTF unfolds G-quadruplex structures genome-wide and removes Cas9 from cleaved DNA ends extended the HIRAN/translocase mechanism to non-fork obstacles, defining HLTF as a general 3′-end-guided protein/structure disruptor.

    Evidence ChIP-seq at G4 sites, in vitro G4 unfolding, PrimPol epistasis, single-molecule Cas9 removal assays, HIRAN mutant validation

    PMID:38987539 PMID:39142279

    Open questions at the time
    • Whether G4 resolution is coupled to PCNA ubiquitination or fork reversal not tested
    • Physiological impact of HLTF-mediated Cas9 removal on genome editing outcomes in therapeutic contexts unknown
  15. 2025 High

    Showing that HLTF attacks unprotected nascent DNA ends in checkpoint-deficient cells, causing irreversible fork collapse, reframed HLTF as a double-edged sword whose fork-remodeling activity becomes cytotoxic when fork protection is compromised.

    Evidence DNA fiber analysis, ssDNA accumulation assays, HLTF KO rescue of checkpoint-deficient cell lethality

    PMID:40578346

    Open questions at the time
    • Signal that distinguishes properly stalled forks from unprotected ones for HLTF engagement not identified
    • Whether pharmacological HLTF inhibition could rescue checkpoint-therapy toxicity not explored
  16. 2025 High

    Identification of HLTF as an H3K23 E3 ubiquitin ligase stimulated by H3K9me3 established a histone-modifying activity that maintains repressive chromatin and suppresses tumor growth, unifying HLTF's chromatin and tumor-suppressor functions under a single enzymatic mechanism.

    Evidence In vitro histone ubiquitination assay, RING mutant analysis, ChIP-seq, ATAC-seq, xenograft tumor models

    PMID:40680746

    Open questions at the time
    • Whether H3K23Ub readers exist that mediate downstream silencing unknown
    • Relationship between H3K23Ub and HLTF's DNA repair functions not examined
  17. 2026 High

    Native mass spectrometry revealed that HLTF exists as an inactive monomer whose ATP-binding site becomes accessible upon DNA fork binding, triggering ATP-dependent dimerization that activates DNA unwinding and fork regression, providing the first allosteric activation model for the full enzyme.

    Evidence Native mass spectrometry, ATPase/unwinding assays, stoichiometry analysis of HLTF–DNA complexes

    PMID:42030070

    Open questions at the time
    • Structure of the active dimer not determined
    • Whether dimerization is required for all HLTF activities (NER eviction, G4 unfolding) or only fork reversal unknown
  18. 2026 High

    Discovery of a HLTF–GATA1 positive feedback loop in erythropoiesis, where HLTF binds the GATA1 promoter and facilitates GATA1 chromatin occupancy while GATA1 transcriptionally activates HLTF, established a lineage-specific transcriptional function and connected HLTF to hematopoietic differentiation.

    Evidence ChIP, CUT&Tag, ATAC-seq, RNA-seq, Co-IP, GATA1 rescue, KO mouse models

    PMID:41521666

    Open questions at the time
    • Whether HLTF's chromatin remodeling at erythroid loci requires its ATPase, RING, or H3K23Ub activity not dissected
    • Relationship to familial MDS mutation E259K not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length HLTF structure — ideally in complex with a fork substrate — is needed to understand how HIRAN recognition, ATPase-driven translocation, dimerization, and RING-mediated ubiquitination are coordinated on the same molecule, and how the enzyme switches between its distinct substrate classes (PCNA, histones, G4s, protein obstacles).
  • No full-length HLTF structure available
  • Mechanism governing substrate selection (PCNA vs. H3 vs. fork DNA vs. G4) unknown
  • In vivo quantitative contribution of each HLTF activity to genome stability not modeled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0016874 ligase activity 5 GO:0140097 catalytic activity, acting on DNA 4 GO:0140657 ATP-dependent activity 4 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3
Pathway
R-HSA-73894 DNA Repair 6 R-HSA-69306 DNA Replication 5 R-HSA-112316 Neuronal System 2 R-HSA-4839726 Chromatin organization 2 R-HSA-1266738 Developmental Biology 1
Partners
FANCJGATA1MSH2PARP1PCNASHPRHUBC13USP7
Complex memberships
p11/annexin A2 heterotetramer

Evidence

Reading pass · 37 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 with the Rad6-Rad18 and Mms2-Ubc13 ubiquitin-conjugating enzyme complexes, and complements UV sensitivity of rad5Δ yeast strains, establishing it as a functional homologue of yeast Rad5. In vitro ubiquitin ligase assay, yeast complementation, Co-IP, cell sensitivity assays Proceedings of the National Academy of Sciences of the United States of America High 18316726 18719106
2008 HLTF interacts with UBC13 and PCNA, and with SHPRH; reduction of HLTF or SHPRH enhances spontaneous mutagenesis; Hltf-deficient MEFs show elevated chromosome breaks and fusions after MMS treatment, indicating HLTF and SHPRH cooperatively maintain genomic stability. Co-IP, siRNA knockdown, mouse embryonic fibroblast chromosomal analysis Proceedings of the National Academy of Sciences of the United States of America High 18719106
2009 HLTF has double-stranded DNA translocase activity that enables replication fork reversal in vitro; in vivo, HLTF promotes restart of replication forks blocked at DNA lesions, dependent on its ATPase/translocase activity. In vitro fork reversal assay, ATPase assay, DNA fiber analysis of labeled chromosomal fibers Molecular and cellular biology High 19948885
2011 HLTF has ATP hydrolysis-dependent protein remodeling activity that can remove proteins (RPA, PCNA, RFC) bound to the replication fork, providing a protein-clearing activity at stalled forks that enables access of damage bypass players. In vitro protein displacement assay, ATPase assay, reconstituted fork substrates Proceedings of the National Academy of Sciences of the United States of America High 21795603
2011 HLTF and SHPRH act in a damage-specific manner: following UV, HLTF enhances PCNA monoubiquitination and recruits TLS polymerase η while inhibiting SHPRH; following MMS, HLTF is degraded and SHPRH interacts with Rad18 and polymerase κ, demonstrating damage-type-specific coordination of PRR branches. siRNA knockdown, Co-IP, PCNA ubiquitination assays, damage sensitivity assays, mutation frequency assays Molecular cell High 21396873
2013 HLTF can catalyze D-loop formation (strand invasion) independently of RAD51 and without ATP binding/hydrolysis; the 3'-end of the invading strand in the D-loop can serve as a primer for DNA polymerase extension, indicating HLTF participates in a RAD51-independent template-switch branch. In vitro D-loop formation assay, DNA polymerase extension assay Nucleic acids research High 24198246
2015 Crystal structure of the HLTF HIRAN domain reveals an OB-fold that specifically recognizes the 3'-hydroxyl end of DNA (both ssDNA and duplex DNA), identifying the HIRAN domain as a sensor of the 3'-end of the primer strand at stalled replication forks that facilitates fork regression. X-ray crystallography of HIRAN-DNA complex, fluorescence polarization binding assays The Journal of biological chemistry High 25858588
2015 The HIRAN domain recruits HLTF to stalled replication forks and provides directional guidance for the dsDNA translocase motor for fork reversal; HIRAN domain mutants retain ubiquitin ligase, ATPase, and dsDNA translocase activities but lose fork-binding and postreplication repair function in cells. Biochemical fork-binding assays, mutagenesis of HIRAN domain, cellular gap-filling assays, structural modeling Nucleic acids research High 26350214
2015 The HIRAN domain of HLTF binds 3' ssDNA ends at stalled replication forks and promotes HLTF-dependent fork reversal in vitro; in cells, HLTF restrains replication fork progression in a HIRAN-dependent manner. Crystal structure of HIRAN-ssDNA complex, biochemical fork reversal assay, DNA fiber analysis, HIRAN mutant cell lines Molecular cell High 26051180
2016 HIV-1 Vpr subverts the DDB1-CUL4-DCAF1 E3 ubiquitin ligase to trigger proteasomal degradation of HLTF in lymphocytic cells and macrophages; this occurs before and independently of Vpr-mediated G2 arrest. Quantitative proteomics, Co-IP, proteasome inhibitor experiments, HIV-1 infection assays Proceedings of the National Academy of Sciences of the United States of America High 27114546
2016 Solution NMR structure of the free HLTF HIRAN domain confirms an OB-like fold; the DNA-binding site of the free domain exhibits conformational heterogeneity compared to DNA-bound structures. Solution NMR structure determination Journal of biomolecular NMR High 27771863
2017 HIV-1 Vpr directly loads HLTF onto the C-terminal WD40 domain of DCAF1 in the CRL4 E3 ubiquitin ligase complex, mediating HLTF polyubiquitination; Vpr interacts with DNA-binding residues in the HIRAN domain of HLTF, with a second contact region connecting HIRAN and ATPase/helicase domains. In vitro reconstitution ubiquitination assays, mutational analysis, pull-down assays The Journal of biological chemistry High 29079575
2018 HLTF ligase activity is stimulated by dsDNA through HIRAN domain-dependent recruitment to stalled primer ends; RFC and PCNA at primer ends suppress en bloc polyubiquitination, redirecting to sequential chain elongation; monoubiquitinated PCNA is immediately polyubiquitinated by coexisting HLTF (coupling reaction), but HLTF added after monoubiquitination requires all three PCNA subunits to be monoubiquitinated for uncoupled polyubiquitination. In vitro PCNA ubiquitination reconstitution assays with defined DNA substrates and mutants Nucleic acids research High 30335157
2018 HLTF accumulates aberrantly at replication forks in FANCJ-knockout cells and contributes to fork degradation; conversely, unrestrained DNA synthesis in HLTF-deficient cells is FANCJ-dependent and correlates with fork degradation, indicating HLTF and FANCJ counteract each other to balance fork remodeling and elongation. iPOND (isolation of proteins on nascent DNA), DNA fiber analysis, FANCJ/HLTF double KO cells Cell reports High 30232006
2019 HLTF restricts HIV-1 replication in activated primary CD4+ T cells; Vpr endows HIV-1 with replication advantage by antagonizing HLTF (and other repair enzymes) via CRL4-DCAF1 E3, demonstrated by Vpr mutation abolishing CRL4-DCAF1 binding that disables HLTF degradation and removes replication advantage. Pairwise HIV-1 replication competition assay, Vpr mutant viruses, primary T cell infection Proceedings of the National Academy of Sciences of the United States of America High 31019079
2020 HLTF-deficient cells fail to undergo replication fork reversal in vivo and rely on PRIMPOL for repriming and unrestrained replication; an HLTF-HIRAN domain mutant instead relies on the TLS protein REV1 for unrestrained replication, demonstrating HLTF promotes fork remodeling and prevents alternative tolerance mechanisms. EM-based fork reversal analysis, DNA fiber assay, PRIMPOL/REV1 epistasis, HLTF HIRAN mutant cells Molecular cell High 32442397
2020 Crystal structure of HIRAN domain bound to duplex DNA shows HIRAN recognizes the 3'-OH of DNA and unexpectedly unwinds three nucleobases of the duplex; Phe-142 is involved in dsDNA binding and strand separation, revealing HIRAN directly participates in fork regression by separating daughter strand from parental template. X-ray crystallography of HIRAN-duplex DNA complex, mutational analysis Journal of biochemistry High 31960921
2020 HLTF contains functional APIM (PCNA-interacting) motifs; direct binding of HLTF to PCNA via APIM is required for HLTF's role in TLS in overexpressing cells and affects mutation spectra, with APIM mutations causing decreased C-to-T transitions and increased mutations on the transcribed strand. APIM mutant constructs, nuclear localization assays, SupF mutagenesis assay International journal of molecular sciences Medium 31973093
2011 USP7 (ubiquitin-specific protease 7) interacts with and deubiquitinates HLTF, stabilizing it after genotoxic stress; USP7-mediated deubiquitination prolongs HLTF half-life, which in turn increases PCNA polyubiquitination. Co-IP, deubiquitination assay, half-life measurement, siRNA knockdown Journal of cellular biochemistry Medium 21845734
2010 CHFR binds to and ubiquitinates HLTF, leading to its proteasomal degradation; HLTF modulates basal expression of PAI-1 (plasminogen activator inhibitor-1), and CHFR overexpression inhibits cell migration by reducing HLTF levels and subsequently decreasing PAI-1 expression. Co-IP, in vitro ubiquitination assay, cell migration assays, PAI-1 expression analysis Biochemical and biophysical research communications Medium 20388495
2009 HLTF interacts with PTIP and RPA70 (both involved in DNA replication and repair); HLTF has in vitro ATPase activity and E3 ubiquitin ligase activity with a range of E2 ubiquitin-conjugating enzymes. Pull-down/Co-IP, in vitro ATPase assay, in vitro ubiquitin ligase assay Biochemical and biophysical research communications Medium 19723507
2022 HLTF facilitates nucleotide excision repair by actively evicting incised damaged DNA together with associated repair proteins; HLTF is recruited to the NER incision complex in a dual-incision-dependent manner via its HIRAN domain binding 3'-OH ssDNA ends, and its translocase motor promotes dissociation of the incision complex and incised oligonucleotide to allow PCNA loading and repair synthesis. In vitro NER reconstitution, HLTF recruitment assays, HIRAN domain mutant analysis, PCNA loading assays Molecular cell High 35271816
2024 HLTF translocase directly removes Cas9 from broken DNA ends after cleavage, allowing DSB processing by end resection or NHEJ; this requires the HIRAN domain and the free 3'-end generated by cleavage of the non-target strand by Cas9 RuvC domain; HLTF removes H840A but not D10A Cas9 nickase. Single molecule assays, bulk biochemical assays, reconstituted reactions, HIRAN domain mutants, cellular CRISPR editing assays Nature communications High 38987539
2024 HLTF is enriched at G4 (G-quadruplex) structures in the human genome, can directly unfold G4s in vitro using its ATP-dependent translocase function, suppresses G4 accumulation throughout the cell cycle, and restrains PrimPol-dependent repriming when G4s are stabilized. ChIP-seq, in vitro G4 unfolding assays, G4 accumulation assays, PrimPol epistasis, DNA fiber analysis Molecular cell High 39142279
2025 When the DNA replication checkpoint is absent, unprotected nascent DNA ends (uncoated by RFC/PCNA) are attacked by HLTF, causing irreversible replication fork collapse and ssDNA hyperaccumulation; loss of HLTF suppresses fork collapse and cell lethality in checkpoint-deficient cells. DNA fiber analysis, ssDNA accumulation assays, HLTF knockdown/knockout in checkpoint-deficient cells Molecular cell High 40578346
2019 A familial MDS-associated HLTF E259K germline mutation reduces HLTF binding to ubiquitin-conjugating enzymes MMS2 and UBC13N, resulting in impaired PCNA polyubiquitination and accumulation of DNA double-strand breaks (γH2AX foci). Whole-exome sequencing, Co-IP of ubiquitin-conjugating enzymes, PCNA ubiquitination assay, γH2AX immunofluorescence Leukemia Medium 30696947
2020 HLTF interacts with PARP1 and both are recruited to damaged replication forks; co-depletion of HLTF and PARP1 increases chromosome breaks and reduces replication track length; HLTF and PARP1 participate in stabilization of damaged forks, while PARP1-BARD1 interaction is involved in repair of collapsed forks. Co-IP, EdU-PLA (proximity ligation assay at forks), DNA fiber analysis, chromosome break analysis Oncogenesis Medium 33281189
2011 In a circadian transcription context, HLTF binds the prolactin promoter E-box and interacts with NONO and SFPQ (identified by mass spectrometry); NONO and SFPQ display circadian patterns and bind rhythmically to the Prl promoter, and their overexpression reduces Prl promoter activity, implicating HLTF as a scaffold for circadian chromatin remodeling. ChIP, mass spectrometry identification of HLTF-associated proteins, promoter activity assays FASEB journal Medium 21507896
2022 HLTF interacts with MSH2 (but not MLH1) in human cells, paralleling yeast Rad5's interaction with Msh2; SHPRH interacts with MLH1, indicating gene duplication led to specialization of MMR-associated roles between the two Rad5 human homologs. Co-IP in human cells, comparison with yeast Rad5 interactions Frontiers in cell and developmental biology Medium 35784486
2013 SMARCA3/HLTF forms a complex with p11/annexin A2 heterotetramer; 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 knockout of SMARCA3. Crystal structure determination, DNA-binding affinity assay, nuclear fractionation, constitutive KO behavioral assays Cell High 23415230
2021 The p11/SMARCA3 complex represses Neurensin-2 transcription in hippocampal parvalbumin interneurons after chronic SSRI treatment; chronic SSRI increases p11 expression, causing SMARCA3 accumulation in the nucleus and consequent Neurensin-2 repression; this pathway regulates AMPA-receptor signaling in parvalbumin interneurons. Cell-type-specific KO, ChIP, nuclear fractionation, electrophysiology Molecular psychiatry Medium 33723417
2025 SMARCA3/HLTF is an E3 ubiquitin ligase that targets histone H3 at lysine 23 (H3K23Ub); SMARCA3's histone ubiquitination activity is stimulated by the repressive H3K9me3 mark; loss of SMARCA3 reduces both H3K23Ub and H3K9me3, increasing chromatin accessibility at promoters/enhancers; RING domain mutant SMARCA3 fails to suppress tumor growth in xenograft models. In vitro histone ubiquitination assay, RING domain mutagenesis, ChIP-seq, ATAC-seq, xenograft tumor models Molecular cell High 40680746
2023 β-TrCP ubiquitin ligase mediates proteasomal degradation of HLTF in hepatocellular carcinoma; HLTF knockdown enhances p62 transcriptional activity and mTOR activation promoting HCC tumorigenesis; HLTF loss-of-function is achieved through this posttranslational mechanism. Co-IP, ubiquitination assay, knockdown functional assays, mTOR inhibitor rescue Journal of molecular cell biology Medium 36822623
2026 HLTF directly binds the GATA1 promoter and enhances GATA1 transcription; HLTF interacts physically with GATA1 and co-occupies erythroid regulatory regions facilitating GATA1 genomic binding; GATA1 also transcriptionally activates HLTF, forming a positive feedback loop; HLTF maintains chromatin accessibility at erythroid gene networks. ChIP, CUT&Tag, ATAC-seq, RNA-seq, Co-IP, GATA1 rescue experiments, KO mouse models Nucleic acids research High 41521666
2026 HLTF exists as an inactive monomer with low ATP accessibility; binding to a DNA fork substrate allosterically modulates HLTF structure to enhance ATP accessibility; ATP induces HLTF dimerization which triggers DNA unwinding activity and subsequent DNA fork regression. Native mass spectrometry, HLTF-DNA complex stoichiometry, ATPase/unwinding assays Journal of the American Chemical Society High 42030070
2025 USP37 interacts with and deubiquitinates RPA at stalled replication forks; USP37 limits HLTF accumulation at replication forks, preventing MRE11-dependent fork degradation; depletion of HLTF reverses replication-associated damage in USP37 knockout cells, placing HLTF downstream of USP37 in fork degradation. Whole-genome CRISPR screen, Co-IP, DNA fiber analysis, HLTF depletion epistasis Nucleic acids research Medium 40548939
2024 DTX2 ubiquitin E3 ligase interacts with HLTF and downregulates HLTF protein levels by increasing its ubiquitination, promoting glioma progression; HLTF loss promotes glioma cell proliferation and migration. Co-IP, in vitro ubiquitination assay, confocal microscopy, KD/OE functional assays, xenograft models Biology direct Medium 38163902

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 234 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 206 18316726
2015 HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal. Molecular cell 172 26051180
2009 Role of double-stranded DNA translocase activity of human HLTF in replication of damaged DNA. Molecular and cellular biology 158 19948885
2020 HLTF Promotes Fork Reversal, Limiting Replication Stress Resistance and Preventing Multiple Mechanisms of Unrestrained DNA Synthesis. Molecular cell 157 32442397
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 121 28954549
2013 SMARCA3, a chromatin-remodeling factor, is required for p11-dependent antidepressant action. Cell 91 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 69 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
2018 Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress. Cell reports 61 30232006
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 61 25858588
2015 Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling. Nucleic acids research 61 26350214
2011 HLTF and SHPRH are not essential for PCNA polyubiquitination, survival and somatic hypermutation: existence of an alternative E3 ligase. DNA repair 53 21269891
2013 Strand invasion by HLTF as a mechanism for template switch in fork rescue. Nucleic acids research 51 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 35 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 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
2011 USP7 regulates the stability and function of HLTF through deubiquitination. Journal of cellular biochemistry 31 21845734
2017 ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells. Autophagy 29 28981387
2013 Role of helicase-like transcription factor (hltf) in the G2/m transition and apoptosis in brain. PloS one 26 23826137
2018 Regulation of HLTF-mediated PCNA polyubiquitination by RFC and PCNA monoubiquitination levels determines choice of damage tolerance pathway. Nucleic acids research 25 30335157
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
2024 HLTF disrupts Cas9-DNA post-cleavage complexes to allow DNA break processing. Nature communications 21 38987539
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 18 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 16 27771863
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
2011 Aberrant methylation of the CpG island of HLTF gene in gastric cardia adenocarcinoma and dysplasia. Clinical biochemistry 14 21531217
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
2025 LINC01088 prevents ferroptosis in glioblastoma by enhancing SLC7A11 via HLTF/USP7 axis. Clinical and translational medicine 12 40000422
2019 Helicase-like transcription factor (Hltf) gene-deletion promotes oxidative phosphorylation (OXPHOS) in colorectal tumors of AOM/DSS-treated mice. PloS one 12 31461471
2025 The DNA replication checkpoint prevents PCNA/RFC depletion to protect forks from HLTF-induced collapse in human cells. Molecular cell 11 40578346
2023 HLTF promotes hepatocellular carcinoma progression by enhancing SRSF1 stability and activating ERK/MAPK pathway. Oncogenesis 11 36670110
2021 Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants. Molecular psychiatry 11 33723417
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
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
2022 Rad5 and Its Human Homologs, HLTF and SHPRH, Are Novel Interactors of Mismatch Repair. Frontiers in cell and developmental biology 8 35784486
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
2025 The SWI/SNF-related protein SMARCA3 is a histone H3K23 ubiquitin ligase that regulates H3K9me3 in cancer. Molecular cell 4 40680746
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
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
2022 DNA Sequence Specificity Reveals a Role of the HLTF HIRAN Domain in the Recognition of Trinucleotide Repeats. Biochemistry 3 35608245
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 1 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