Affinage

HAP1

DNA repair nuclease/redox regulator APEX1 · UniProt P27695

Length
318 aa
Mass
35.6 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HAP1 (huntingtin-associated protein 1) is a brain-enriched cytoplasmic adaptor that couples membranous cargo to the cytoskeletal motor machinery to drive intracellular and axonal trafficking (PMID:9361024, PMID:9742138). It associates with microtubules and a wide range of organelles—mitochondria, ER, endosomes/lysosomes, and synaptic vesicles—mirroring the distribution of huntingtin, with which it binds in a polyglutamine-length-dependent manner, and it concentrates into stigmoid-body cytoplasmic inclusions whose formation depends specifically on the self-associating HAP1-A isoform (PMID:9742138, PMID:9668110, PMID:9798945). Mechanistically, HAP1 bridges cargo to both retrograde (dynein/dynactin via p150Glued) and anterograde (kinesin KIF5) motors: it transports GABAA receptors to synapses and supports their recycling, moves autophagosomes for processive retrograde transport and efficient cargo degradation, and traffics proBDNF in a trimeric complex with sortilin to facilitate furin processing of mature BDNF (PMID:9361024, PMID:20152113, PMID:24453320, PMID:21357693). HAP1 is also required for BDNF/TrkB endocytosis and downstream ERK/Akt/PLCγ signaling, and engages clathrin light chain B and Sec23A to support general endocytosis and vesicle retrieval (PMID:28083816, PMID:28259758). Beyond trafficking, HAP1 forms a ternary complex with huntingtin and the InsP3R to mediate ER Ca2+ release (PMID:15379999, PMID:30819925), promotes autophagy initiation by facilitating PtdIns3K complex assembly (and is itself a UBE3A ubiquitination substrate) (PMID:31445164), regulates ciliogenesis through PCM1 trafficking (PMID:21985783), and constrains neuronal mTORC1 activity as a Tsc1 partner (PMID:24227713). In vivo, HAP1 governs hypothalamic/brainstem feeding behavior—its loss causes postnatal starvation and lethality rescued by neuronal re-expression—and postnatal hippocampal neurogenesis via stabilization of c-kit and competition with DYRK1A for Dcaf7 (PMID:11971876, PMID:15496430, PMID:25875952, PMID:28137862). Polyglutamine-expanded huntingtin disrupts these HAP1-dependent functions, and HAP1 normally sequesters N-terminal huntingtin away from Rhes-mediated sumoylation and striatal neurotoxicity (PMID:20152113, PMID:32747555).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Established HAP1 as a physical adaptor linking huntingtin and vesicles to the motor/cytoskeletal machinery, framing its core trafficking role.

    Evidence GST pulldown and co-IP from brain showing HAP1–p150Glued/dynactin binding, plus yeast two-hybrid linking HAP1 to a Rac1-GEF (Duo)

    PMID:9285789 PMID:9361024

    Open questions at the time
    • Direct demonstration of motor-driven cargo movement not yet shown in 1997
    • Functional consequence of the Duo/Rac1 interaction unresolved
  2. 1998 High

    Defined HAP1's subcellular distribution and polyQ-dependent huntingtin binding, and identified isoform-specific control of stigmoid-body inclusion formation.

    Evidence Immunogold EM and fractionation in brain; in vitro binding/co-IP with polyQ-length dependence; yeast two-hybrid and transfection of HAP1-A/B self-association

    PMID:9668110 PMID:9742138 PMID:9798945

    Open questions at the time
    • Functional purpose of stigmoid bodies unresolved
    • Whether organelle association is direct or motor-mediated not distinguished
  3. 2002 High

    Demonstrated an essential physiological role in vivo: HAP1 is required for postnatal feeding and survival, localizing function to the hypothalamus.

    Evidence Homozygous Hap1 knockout mice with feeding/lethality phenotype and leptin measurement

    PMID:11971876

    Open questions at the time
    • Molecular mechanism connecting HAP1 to feeding not defined
    • Cell-type responsible not yet pinpointed
  4. 2004 High

    Pinpointed the feeding/survival requirement to neuronal HAP1 and established HAP1 as required for huntingtin-dependent InsP3R1 Ca2+ release.

    Evidence Conditional neuronal gene-repair rescue and epistasis in mice; planar lipid bilayer electrophysiology and Ca2+ imaging in HAP1−/− striatal neurons

    PMID:15379999 PMID:15496430

    Open questions at the time
    • Identity of the responsible neuronal circuit incomplete
    • Whether HAP1 binds InsP3R directly not established here
  5. 2003 Medium

    Extended HAP1's adaptor logic into transcriptional regulation, acting with huntingtin as a scaffold for MLK2-mediated NeuroD activation.

    Evidence Yeast two-hybrid, co-IP, reporter and kinase assays

    PMID:12881483

    Open questions at the time
    • In vivo relevance to neuronal differentiation not shown
    • Single-lab finding without genetic confirmation
  6. 2010 High

    Resolved a defined anterograde transport pathway: HAP1–KIF5 carries GABAA receptors to synapses, with functional consequences for inhibitory transmission.

    Evidence Co-IP, dominant-negative complex disruption, IPSC electrophysiology, and synaptic receptor imaging; brainstem Hap1-Ahi1 insulin-sensing study

    PMID:20152113 PMID:21146532

    Open questions at the time
    • How cargo selectivity is achieved unresolved
    • Mechanism by which Hap1-Ahi1 senses insulin not defined (Medium-confidence feeding study)
  7. 2011 High

    Broadened HAP1's trafficking repertoire to neurotrophin handling and ciliogenesis, defining specific complexes and interaction domains.

    Evidence FRET/Co-IP/GST domain mapping and FRAP rescue for proBDNF–HAP1–sortilin; conditional Htt knockout mice and cilia/hydrocephalus readouts for HTT–HAP1–PCM1; in vivo knockdown linking Mecp2 to Htt/Hap1-dependent BDNF axonal transport

    PMID:21357693 PMID:21985783 PMID:22127389

    Open questions at the time
    • Direct HAP1–PCM1 binding interface not mapped
    • Mecp2/Hap1 axonal transport study is Medium confidence
  8. 2014 High

    Established that HAP1 regulates autophagosome motility, distinguishing transport from formation and linking it to mitochondrial cargo clearance.

    Evidence Copurification, live GFP-LC3 imaging, and RNAi in primary neurons with mitochondrial degradation assay

    PMID:24453320

    Open questions at the time
    • How HAP1 coordinates dynein/kinesin directionality on autophagosomes unresolved
  9. 2017 High

    Consolidated HAP1 as an endocytic and recycling adaptor for receptors and surface proteins, with direct coat-machinery partners.

    Evidence Co-IP/GST/MS identifying clathrin light chain B and Sec23A and transferrin endocytosis in KO neurons; HAP1–p75NTR/TrkB complex and BDNF/TrkB internalization plus signaling in KO neurons; OGD-induced calpain cleavage and GABAAR recycling assays

    PMID:26732589 PMID:28083816 PMID:28259758

    Open questions at the time
    • Whether HAP1 directly nucleates clathrin coats versus stabilizing cargo unresolved
    • OGD recycling study is Medium confidence
  10. 2017 High

    Placed HAP1 in a hypothalamic growth-regulatory pathway through competitive control of Dcaf7/DYRK1A.

    Evidence Stigmoid-body proteomics, competitive co-IP, and AAV-DYRK1A overexpression phenocopying Hap1 loss in mice

    PMID:28137862

    Open questions at the time
    • Mechanism connecting Dcaf7 nuclear translocation to growth not defined
  11. 2013 High

    Identified HAP1 as a Tsc1 partner restraining mTORC1 to control neuronal polarity and positioning.

    Evidence Interaction proteomics, in utero electroporation knockdown, and mTORC1-inhibitor epistasis rescue

    PMID:24227713

    Open questions at the time
    • How HAP1 stabilizes Tsc1 protein mechanistically unresolved
  12. 2015 High

    Linked HAP1 to postnatal hippocampal neurogenesis and mood via stabilization of c-kit.

    Evidence Conditional/inducible Hap1 knockout, neurogenesis markers, and AAV-c-kit rescue of behavior

    PMID:25875952

    Open questions at the time
    • Biochemical basis of HAP1-mediated c-kit stabilization not defined
  13. 2019 High

    Connected HAP1 to autophagy initiation and Ca2+-dependent cell death, including disease contexts in Angelman syndrome and leukemia.

    Evidence SILAM proteomics/ubiquitination and PtdIns3K activity assays with KD rescue in AS neurons; genome-wide RNAi, ternary HTT–InsP3R complex co-IP, and Ca2+/apoptotic assays in ALL cells

    PMID:30819925 PMID:31445164

    Open questions at the time
    • How UBE3A-mediated ubiquitination alters HAP1 function not fully defined
    • Direct architecture of the HTT–HAP1–InsP3R ternary complex not structurally resolved
  14. 2020 High

    Revealed a neuroprotective role in which HAP1 sequesters mutant huntingtin away from Rhes-mediated sumoylation, preventing striatal neurodegeneration.

    Evidence AAV Hap1 depletion in HD knock-in mice with neuronal-loss histology and Rhes–HTT/sumoylation biochemistry

    PMID:32747555

    Open questions at the time
    • Whether sequestration occurs within stigmoid bodies not directly shown
    • Therapeutic relevance to human HD untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HAP1 selects among its many cargoes and coordinates opposing motors, and the structural basis of stigmoid-body assembly, remain unresolved.
  • No structural model of HAP1 cargo/motor complexes
  • Mechanism distinguishing HAP1-A versus HAP1-B functional partitioning incompletely defined
  • Rules governing cargo-specific recruitment unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0031410 cytoplasmic vesicle 3 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005856 cytoskeleton 2 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 2
Partners
DCAF7/WDR68HTTKIF5P150GLUED/DCTN1PCM1SORTILINTRKBTSC1
Complex memberships
HAP1–KIF5 motor complexHAP1–huntingtin–InsP3R ternary complexproBDNF–HAP1–sortilin complexstigmoid body

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 HAP1 interacts with the p150Glued subunit of dynactin. Binding was confirmed in vitro by pulldown of p150Glued (amino acids 879-1150) to a HAP1-GST fusion protein, and HAP1 co-immunoprecipitated with p150Glued from brain extracts. Both proteins are enriched in a nerve terminal vesicle-rich fraction and partially co-localize in NGF-treated PC12 cells, suggesting HAP1 acts as an adaptor linking huntingtin/vesicles to cytoskeletal motor machinery. GST pulldown (in vitro), co-immunoprecipitation from brain extracts, subcellular fractionation, confocal co-localization in PC12 cells Human molecular genetics High 9361024
1997 HAP1 interacts with a Trio-like polypeptide (Duo) containing a Rac1 guanine nucleotide exchange factor domain, a pleckstrin homology domain, and spectrin-like repeats. Interaction was identified by yeast two-hybrid and confirmed by in vitro protein-binding assay, suggesting HAP1 connects huntingtin to a Ras-related signaling pathway. Yeast two-hybrid screen, in vitro protein-binding assay Human molecular genetics Medium 9285789
1998 HAP1 is a cytoplasmic protein that associates with microtubules and multiple membranous organelles including mitochondria, endoplasmic reticulum, tubulovesicles, endosomal/lysosomal organelles, and synaptic vesicles in rat and human brain neurons. Subcellular fractionation and immunogold electron microscopy demonstrated near-identical organelle associations for HAP1 and huntingtin. HAP1 also concentrates in stigmoid bodies (nucleolus-like cytoplasmic inclusions) in ventral forebrain neurons. Immunogold electron microscopy, subcellular fractionation, light microscopic immunocytochemistry The Journal of neuroscience High 9742138
1998 Human HAP1 (hHAP) binds huntingtin in vitro and the interaction is enhanced by lengthening the glutamine repeat. In vitro binding, immunoprecipitation, and co-expression studies confirmed the interaction. hHAP is expressed specifically in human brain as a 75 kDa protein encoded by a 4.1 kb transcript. In vitro binding assay, co-immunoprecipitation, co-expression in cell lines The Journal of biological chemistry High 9668110
1998 HAP1-A and HAP1-B isoforms both self-associate (homo- and hetero-multimerize) as shown by yeast two-hybrid and transfection studies. HAP1-A, but not HAP1-B, is essential for formation of HAP1-immunoreactive cytoplasmic inclusions (stigmoid bodies). The ratio of HAP1-A to HAP1-B expressed in HEK293 cells regulates the formation of these inclusions. Yeast two-hybrid, transfection and immunofluorescence in cell lines, co-expression assays Journal of neurochemistry Medium 9798945
2002 Targeted disruption of Hap1 in mice causes postnatal death due to depressed feeding behavior. Hap1−/− pups show markedly decreased milk ingestion, starvation, and 100% lethality by postnatal day 9. HAP1 is particularly enriched in the hypothalamus, implicating HAP1 in hypothalamus-dependent regulation of postnatal feeding behavior. Gene targeting (homozygous knockout mice), behavioral analysis of feeding, serum leptin measurement, brain weight analysis Human molecular genetics High 11971876
2003 HAP1 interacts with NeuroD, a basic helix-loop-helix transcription factor, via yeast two-hybrid. HAP1 facilitates the activation of NeuroD by MLK2 kinase, and huntingtin interacts with NeuroD via HAP1. HAP1 and huntingtin function as a scaffold complex that promotes MLK2-mediated phosphorylation and stimulation of NeuroD transcriptional activity. Yeast two-hybrid, co-immunoprecipitation, reporter gene assays for NeuroD transcriptional activity, kinase assays Proceedings of the National Academy of Sciences of the United States of America Medium 12881483
2004 HAP1 is required for the potentiation of InsP3R1-mediated Ca2+ release by mutant huntingtin in medium spiny striatal neurons. Using HAP1−/− mice, HAP1A was shown to facilitate functional effects of huntingtin and expanded huntingtin on the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) in planar lipid bilayers, and HAP1 is required for changes in basal Ca2+ levels caused by huntingtin overexpression in MSN. HAP1 knockout mice, planar lipid bilayer electrophysiology, Ca2+ imaging in primary striatal neurons The European journal of neuroscience High 15379999
2004 Conditional rescue of Hap1 expression in neuronal cells (using a conditional gene repair strategy) before birth is sufficient to rescue the early postnatal lethality of Hap1 null mice, demonstrating that Hap1 function in neurons is responsible for the feeding/survival phenotype. No synergism was observed between Hap1 and huntingtin mutations during mouse development. Conditional gene repair strategy (neuronal rescue), genetic epistasis analysis in double-mutant mice Human molecular genetics High 15496430
2006 HAP1 interacts with the androgen receptor (AR) through its ligand-binding domain in a polyglutamine-length-dependent manner and forms cytoplasmic inclusions (stigmoid bodies) that sequester polyQ-expanded AR. Co-transfection with HAP1 suppresses SBMA-mutant ARQ65-induced apoptosis. Dihydrotestosterone reduces HAP1-ARQ25 association more than HAP1-ARQ65 association. Co-transfection in HEp-2 cells, co-immunoprecipitation, immunofluorescence, apoptosis assays Human molecular genetics Medium 16782802
2007 HAP1 binds directly to the conserved TBP(CORE) domain of TATA-binding protein (TBP), as shown by yeast two-hybrid and domain mapping (HAP1 residues 157–261 and 473–582 both mediate binding). Co-expression in mammalian cells causes sequestration of a subset of TBP into HAP1 cytoplasmic stigmoid-like bodies, reducing nuclear TBP levels. The TBP polyQ repeat length (but not polyQ expansion) quantitatively influences the proportion of TBP assembled into STLBs. Yeast two-hybrid, domain mapping, co-expression with fluorescent tags in COS-7/293/Neuro-2a cells, immunofluorescence BMC molecular biology Medium 17868456
2010 HAP1 and KIF5 (kinesin family motor protein 5) form a complex that transports GABAA receptors (GABAARs) to synapses. Disrupting the HAP1-KIF5 complex decreases synaptic GABAAR number and reduces the amplitude of inhibitory postsynaptic currents. Mutant huntingtin reduces GABAAR transport and inhibitory synaptic currents via disruption of this pathway. Co-immunoprecipitation, dominant-negative disruption of HAP1-KIF5 complex, electrophysiology (IPSCs), immunofluorescence quantification of synaptic GABAARs Neuron High 20152113
2011 HAP1 interacts with pericentriolar material 1 protein (PCM1), and the huntingtin-HAP1-PCM1 pathway regulates ciliogenesis. Loss of Htt in mouse cells impaired retrograde trafficking of PCM1, reducing primary cilia formation. Deletion of Htt in ependymal cells led to PCM1 mislocalization, altered cilia layer, and hydrocephalus. In HD, pathogenic polyQ expansion caused centrosomal accumulation of PCM1 and abnormally long primary cilia. Cell imaging (live and fixed), conditional knockout mice (ependymal-specific Htt deletion), immunofluorescence, cilia length measurement, cerebrospinal fluid flow analysis The Journal of clinical investigation High 21985783
2011 proBDNF forms a trimeric complex with HAP1 and sortilin that regulates proBDNF intracellular trafficking, stabilization, and processing. FRET and co-immunoprecipitation confirmed HAP1–proBDNF and sortilin–proBDNF interactions in HEK293 cells and co-localization (>90%) in cortical neurons. GST pulldown mapped the HAP1-proBDNF interaction to HAP1 residues 371–445 and proBDNF residues 65–90. HAP1 knockout neurons showed defective proBDNF vesicle movement in neurites (assessed by FRAP), which was partially restored by HAP1 re-expression and further rescued by co-introduction of HAP1 and sortilin. The complex facilitates furin cleavage to release mature BDNF. FRET, co-immunoprecipitation, GST pulldown domain mapping, FRAP in HAP1−/− neurons, Western blot The Journal of biological chemistry High 21357693
2011 Mecp2 deficiency downregulates Htt and Hap1 expression in mouse brain, causing a defect in BDNF axonal transport along the corticostriatal pathway that is dependent on the Htt/Hap1 pathway. Hap1 knockdown in vivo reduced BDNF vesicle velocity in Mecp2-deficient axons; re-expression of Mecp2 rescued the transport defect. APP transport, also Htt/Hap1-dependent, was similarly impaired. In vivo AAV/RNAi knockdown, live axonal transport imaging (velocity measurement), Western blot, Mecp2 KO mice Neurobiology of disease Medium 22127389
2014 Huntingtin (htt) and HAP1 copurify and colocalize with autophagosomes in neurons. Using live-cell imaging and RNAi in primary GFP-LC3 transgenic neurons, htt and HAP1 were shown to control autophagosome dynamics by regulating dynein and kinesin motors to promote processive retrograde axonal transport. htt is not required for autophagosome formation or cargo loading, but htt or HAP1 depletion causes defective autophagosome transport correlated with inefficient degradation of engulfed mitochondrial fragments. Biochemical copurification, live-cell imaging with GFP-LC3, RNAi knockdown in primary neurons from transgenic mice, mitochondrial cargo degradation assay The Journal of neuroscience High 24453320
2015 Early postnatal (but not adult) depletion of Hap1 reduces hippocampal neurogenesis in the dentate gyrus and causes adult depressive-like behavior. Hap1 stabilizes c-kit (a protein expressed in neuroproliferative zones). AAV-mediated c-kit expression in the hippocampus promoted postnatal neurogenesis and ameliorated the depressive-like phenotype in conditional Hap1 KO mice, placing Hap1 upstream of c-kit in a postnatal neurogenesis pathway. Conditional/inducible Hap1 knockout mice (various ages/regions), behavioral assays (depressive-like behavior), BrdU/neurogenesis markers, stereotaxic AAV injection for c-kit rescue PLoS genetics High 25875952
2016 HAP1 maintains GABAAR surface expression by promoting receptor recycling. OGD (oxygen-glucose deprivation) induced calpain-mediated cleavage of HAP1, reduced HAP1–GABAAR β3 interaction, and decreased receptor recycling. Transfection of HAP1A or HAP1B restored GABAAR β3 surface expression after OGD; HAP1A specifically maintained the rate of receptor recycling. HAP1 transfection significantly decreased OGD-induced neuronal death. OGD model in hippocampal neurons, myc-tagged GABAAR β3 trafficking assay, co-immunoprecipitation, transfection overexpression, cell viability assays Molecular neurobiology Medium 26732589
2017 HAP1 interacts with clathrin light chain B (validated by co-immunoprecipitation and GST binding assay) and co-localizes with it in cells. HAP1 also interacts with Sec23A (ER-to-Golgi COPII coat component), validated by endogenous Co-IP in rat brain homogenate. HAP1 depletion dramatically reduces vesicle retrieval and endocytosis in adrenal chromaffin cells, and HAP1−/− cortical neurons show impaired transferrin endocytosis. HAP1-GST affinity chromatography with mass spectrometry, co-immunoprecipitation (endogenous and overexpressed), GST-binding assay, immunofluorescence co-localization, transferrin endocytosis assay in HAP1−/− neurons, exocytosis/endocytosis assay in chromaffin cells Cellular signalling High 28259758
2017 HAP1 is required for BDNF and TrkB endocytosis in neurons. HAP1 forms a complex with p75NTR, TrkB, and newly endocytosed BDNF (co-immunoprecipitation). BDNF and TrkB internalization is abolished in HAP1 KO cortical neurons. TrkB downstream signaling (ERK, Akt, PLCγ-1) is impaired in HAP1 KO neurons upon BDNF stimulation. HAP1 KO also impairs cerebellar granule cell proliferation in vitro and in vivo. Co-immunoprecipitation, HAP1 KO neurons, receptor internalization assay, Western blot for signaling pathway activation, cell proliferation assay, in vivo cerebellum analysis Molecular neurobiology High 28083816
2017 Hap1 binds Dcaf7/WDR68 in cytoplasm and regulates its nuclear translocation. Hap1 competes with DYRK1A for Dcaf7 binding; depleting Hap1 promotes the DYRK1A-Dcaf7 interaction and increases DYRK1A protein level. In transgenic Down syndrome mice overexpressing DYRK1A, Hap1-Dcaf7 association in the hypothalamus is reduced. Overexpression of DYRK1A in the hypothalamus leads to delayed postnatal growth, phenocopying Hap1 loss. Immunoprecipitation from stigmoid body-enriched brain fraction (mass spectrometry), co-immunoprecipitation, competitive binding assay, AAV-mediated DYRK1A overexpression in vivo, transgenic DS mouse analysis, growth measurement Proceedings of the National Academy of Sciences of the United States of America High 28137862
2019 HAP1 is an in vivo ubiquitination target of UBE3A E3 ligase. HAP1 promotes autophagy initiation by facilitating PtdIns3K complex formation and enhancing its activity. HAP1 co-localizes with LC3 and other autophagosome expansion proteins; HAP1 overexpression increases autophagy flux. HAP1 knockdown alleviated aberrant autophagy and synaptic deficits in Angelman syndrome (AS) neurons. Quantitative proteomics (SILAM) in Ube3a mutant mice, ubiquitination assay, PtdIns3K activity assay, autophagy flux measurement, HAP1 KD in AS neurons, dendritic spine density analysis Neurobiology of disease High 31445164
2019 HAP1 forms a ternary complex with huntingtin and InsP3R (inositol 1,4,5-triphosphate receptor) that mediates ER Ca2+ release. Loss of HAP1 prevents formation of this ternary complex, blocks l-asparaginase-mediated ER Ca2+ release and external Ca2+ entry, reduces activation of calpain-1, Bid, and caspases-3/12, and thereby confers l-asparaginase resistance in ALL cells. Genome-wide RNAi screen, co-immunoprecipitation (ternary complex), Ca2+ imaging, calpain/caspase activity assays, BAPTA-AM pharmacological rescue, analysis of ALL patient samples Blood High 30819925
2020 AAV-mediated depletion of Hap1 in adult HD knock-in mouse brains leads to selective neuronal loss in the striatum requiring the presence of mutant HTT. When Hap1 is absent, Rhes (a striatum-enriched GTPase) binds more N-terminal HTT, and more soluble and sumoylated N-terminal HTT accumulates in the striatum, indicating Hap1 normally sequesters HTT away from Rhes-mediated sumoylation and neurotoxicity. AAV-mediated Hap1 depletion in HD KI mice, histological analysis of neuronal loss, co-immunoprecipitation (Rhes-HTT), sumoylation assay, Western blot for N-terminal HTT Proceedings of the National Academy of Sciences of the United States of America High 32747555
2013 Hap1 is a functional partner of Tsc1 in neurons. Hap1 knockdown in hippocampal neurons promotes specification of supernumerary axons and impairs pyramidal neuron positioning in mouse hippocampus in vivo, phenocopying Tsc1 knockdown. Hap1 knockdown downregulates Tsc1 protein and stimulates mTORC1 activity (S6 phosphorylation). Inhibition of mTORC1 suppresses the Hap1 knockdown-induced polarity phenotype. Interaction proteomics (co-immunoprecipitation in neural cells), in utero electroporation knockdown, immunofluorescence analysis of axon number and neuron positioning, Western blot for mTORC1 pathway, mTORC1 inhibitor rescue The Journal of neuroscience High 24227713
2010 The Hap1-Ahi1 complex in the brainstem functions as a sensor for insulin signals regulating feeding behavior. Fasting, 2-deoxy-D-glucose treatment, and streptozotocin-induced insulin reduction each upregulated Hap1-Ahi1 in brainstem. Intra-brain insulin injection decreased Hap1-Ahi1 expression. RNAi knockdown of brainstem Hap1 decreased food intake and body weight in mice. Western blot under fasting/pharmacological conditions, intra-brain insulin injection, RNAi knockdown with feeding behavior measurement FEBS letters Medium 21146532

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. The Journal of neuroscience : the official journal of the Society for Neuroscience 305 24453320
1997 The crystal structure of the human DNA repair endonuclease HAP1 suggests the recognition of extra-helical deoxyribose at DNA abasic sites. The EMBO journal 283 9351835
1989 Functional dissection and sequence of yeast HAP1 activator. Cell 280 2643482
1997 Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Human molecular genetics 277 9361024
1987 Yeast HAP1 activator binds to two upstream activation sites of different sequence. Cell 255 3030565
1993 Identification of residues in the human DNA repair enzyme HAP1 (Ref-1) that are essential for redox regulation of Jun DNA binding. Molecular and cellular biology 250 8355688
2010 Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron 212 20152113
1994 A role for the human DNA repair enzyme HAP1 in cellular protection against DNA damaging agents and hypoxic stress. Nucleic acids research 200 7800476
1987 Yeast HAP1 activator competes with the factor RC2 for binding to the upstream activation site UAS1 of the CYC1 gene. Cell 196 3030567
1998 Identification of APN2, the Saccharomyces cerevisiae homolog of the major human AP endonuclease HAP1, and its role in the repair of abasic sites. Genes & development 180 9765213
1999 Molecular mechanism of heme signaling in yeast: the transcriptional activator Hap1 serves as the key mediator. Cellular and molecular life sciences : CMLS 166 11212295
2006 Global structural changes in hepatitis B virus capsids induced by the assembly effector HAP1. Journal of virology 150 16943288
1998 The cellular and subcellular localization of huntingtin-associated protein 1 (HAP1): comparison with huntingtin in rat and human. The Journal of neuroscience : the official journal of the Society for Neuroscience 143 9742138
2011 Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. The Journal of clinical investigation 131 21985783
1996 Huntingtin-associated protein (HAP1): discrete neuronal localizations in the brain resemble those of neuronal nitric oxide synthase. Proceedings of the National Academy of Sciences of the United States of America 121 8643490
1995 Identification of critical active-site residues in the multifunctional human DNA repair enzyme HAP1. Nature structural biology 120 7664124
1999 A 'natural' mutation in Saccharomyces cerevisiae strains derived from S288c affects the complex regulatory gene HAP1 (CYP1). Current genetics 119 10541856
1997 Huntingtin-associated protein 1 (HAP1) binds to a Trio-like polypeptide, with a rac1 guanine nucleotide exchange factor domain. Human molecular genetics 117 9285789
1995 Site-directed mutagenesis of the human DNA repair enzyme HAP1: identification of residues important for AP endonuclease and RNase H activity. Nucleic acids research 110 7784208
2007 Heme levels switch the function of Hap1 of Saccharomyces cerevisiae between transcriptional activator and transcriptional repressor. Molecular and cellular biology 108 17785431
1992 HAP1 and ROX1 form a regulatory pathway in the repression of HEM13 transcription in Saccharomyces cerevisiae. Molecular and cellular biology 105 1588959
2002 A microarray-assisted screen for potential Hap1 and Rox1 target genes in Saccharomyces cerevisiae. Yeast (Chichester, England) 103 12112237
2001 Nuclear expression of human apurinic/apyrimidinic endonuclease (HAP1/Ref-1) in head-and-neck cancer is associated with resistance to chemoradiotherapy and poor outcome. International journal of radiation oncology, biology, physics 93 11316543
1994 The yeast activator HAP1--a GAL4 family member--binds DNA in a directly repeated orientation. Genes & development 91 7958882
1999 Structure of a HAP1-DNA complex reveals dramatically asymmetric DNA binding by a homodimeric protein. Nature structural biology 85 9886294
2004 Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: neuronal selectivity and potential neuroprotective role of HAP1. Human molecular genetics 84 15548548
1988 Co-ordinate control of synthesis of mitochondrial and non-mitochondrial hemoproteins: a binding site for the HAP1 (CYP1) protein in the UAS region of the yeast catalase T gene (CTT1). The EMBO journal 77 2844525
2002 Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior. Human molecular genetics 73 11971876
1991 Regulation of the yeast CYT1 gene encoding cytochrome c1 by HAP1 and HAP2/3/4. Molecular and cellular biology 73 1656218
1998 Expression and subcellular localization of human AP endonuclease 1 (HAP1/Ref-1) protein: a basis for its role in human disease. Histopathology 72 9870152
2002 The yeast transcriptome in aerobic and hypoxic conditions: effects of hap1, rox1, rox3 and srb10 deletions. Molecular microbiology 71 11929514
2003 A mechanism of oxygen sensing in yeast. Multiple oxygen-responsive steps in the heme biosynthetic pathway affect Hap1 activity. The Journal of biological chemistry 67 14512429
1998 A human HAP1 homologue. Cloning, expression, and interaction with huntingtin. The Journal of biological chemistry 63 9668110
2005 HAP1 and intracellular trafficking. Trends in pharmacological sciences 62 15629196
2000 Ultraviolet B radiation-induced skin cancer in mice defective in the Xpc, Trp53, and Apex (HAP1) genes: genotype-specific effects on cancer predisposition and pathology of tumors. Cancer research 62 10749126
2011 Precursor of brain-derived neurotrophic factor (proBDNF) forms a complex with Huntingtin-associated protein-1 (HAP1) and sortilin that modulates proBDNF trafficking, degradation, and processing. The Journal of biological chemistry 61 21357693
2003 Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2. Proceedings of the National Academy of Sciences of the United States of America 61 12881483
1993 Evidence for an interaction between the CYP1(HAP1) activator and a cellular factor during heme-dependent transcriptional regulation in the yeast Saccharomyces cerevisiae. The EMBO journal 61 8458333
1991 Complex transcriptional regulation of the Saccharomyces cerevisiae CYB2 gene encoding cytochrome b2: CYP1(HAP1) activator binds to the CYB2 upstream activation site UAS1-B2. Molecular and cellular biology 61 2046677
2011 Modification of Mecp2 dosage alters axonal transport through the Huntingtin/Hap1 pathway. Neurobiology of disease 55 22127389
2004 HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca release in primary culture of striatal medium spiny neurons. The European journal of neuroscience 55 15379999
1992 Structure of the human DNA repair gene HAP1 and its localisation to chromosome 14q 11.2-12. Nucleic acids research 55 1383925
2000 Substitution of Asp-210 in HAP1 (APE/Ref-1) eliminates endonuclease activity but stabilises substrate binding. Nucleic acids research 54 10871340
1994 HAP1 is nuclear but is bound to a cellular factor in the absence of heme. The Journal of biological chemistry 54 8182072
1992 HAP1 positive control mutants specific for one of two binding sites. Genes & development 51 1327959
2005 Polymerase chain reaction assay specific for pathogenic Leptospira based on the gene hap1 encoding the hemolysis-associated protein-1. FEMS microbiology letters 50 15686847
1998 Association of HAP1 isoforms with a unique cytoplasmic structure. Journal of neurochemistry 48 9798945
1993 Antibody-promoted dimerization bypasses the regulation of DNA binding by the heme domain of the yeast transcriptional activator HAP1. Proceedings of the National Academy of Sciences of the United States of America 48 8464899
2006 Huntingtin-associated protein 1 (HAP1) interacts with androgen receptor (AR) and suppresses SBMA-mutant-AR-induced apoptosis. Human molecular genetics 47 16782802
1996 Mutations in target DNA elements of yeast HAP1 modulate its transcriptional activity without affecting DNA binding. Nucleic acids research 45 8628677
2001 The Hsp70-Ydj1 molecular chaperone represses the activity of the heme activator protein Hap1 in the absence of heme. Molecular and cellular biology 44 11689685
1998 The expression of Huntingtin-associated protein (HAP1) mRNA in developing, adult and ageing rat CNS: implications for Huntington's disease neuropathology. The European journal of neuroscience 44 9751154
1996 Asparagine 212 is essential for abasic site recognition by the human DNA repair endonuclease HAP1. Nucleic acids research 44 8932375
1991 CYP1 (HAP1) is a determinant effector of alternative expression of heme-dependent transcribed genes in yeast [corrected]. Molecular & general genetics : MGG 42 1715975
2004 Huntingtin-associated protein 1 (Hap1) mutant mice bypassing the early postnatal lethality are neuroanatomically normal and fertile but display growth retardation. Human molecular genetics 41 15496430
2000 Functional analysis of heme regulatory elements of the transcriptional activator Hap1. Biochemical and biophysical research communications 41 10873649
1986 The overproducing CYP1 and the underproducing hap1 mutations are alleles of the same gene which regulates in trans the expression of the structural genes encoding iso-cytochromes c. Current genetics 41 2832070
2001 The HAP1 protein stimulates the turnover of human mismatch-specific thymine-DNA-glycosylase to process 3,N(4)-ethenocytosine residues. Mutation research 40 11506820
1996 The C6 zinc cluster dictates asymmetric binding by HAP1. The EMBO journal 39 8887558
1994 Evidence that TUP1/SSN6 has a positive effect on the activity of the yeast activator HAP1. Genetics 39 8005436
2010 Age at onset in Huntington's disease: replication study on the associations of ADORA2A, HAP1 and OGG1. Neurogenetics 38 20512606
2019 HAP1 loss confers l-asparaginase resistance in ALL by downregulating the calpain-1-Bid-caspase-3/12 pathway. Blood 37 30819925
2004 A hap1 mutation in a laboratory strain of Saccharomyces cerevisiae results in decreased expression of ergosterol-related genes and cellular ergosterol content compared to sake yeast. Journal of bioscience and bioengineering 37 16233684
1994 The yeast SIN3 gene product negatively regulates the activity of the human progesterone receptor and positively regulates the activities of GAL4 and the HAP1 activator. Molecular & general genetics : MGG 37 7830720
1999 A new class of repression modules is critical for heme regulation of the yeast transcriptional activator Hap1. Molecular and cellular biology 36 10330173
2005 The heme activator protein Hap1 represses transcription by a heme-independent mechanism in Saccharomyces cerevisiae. Genetics 34 15654089
1998 Differential cleavage of oligonucleotides containing the benzene-derived adduct, 1,N6-benzetheno-dA, by the major human AP endonuclease HAP1 and Escherichia coli exonuclease III and endonuclease IV. Carcinogenesis 34 9744526
1997 The structure and functions of the HAP1/Ref-1 protein. Oncology research 34 9406232
2020 Loss of Hap1 selectively promotes striatal degeneration in Huntington disease mice. Proceedings of the National Academy of Sciences of the United States of America 33 32747555
2020 Efficient and crucial quality control of HAP1 cell ploidy status. Biology open 33 33184093
1999 Overexpression of the human HAP1 protein sensitizes cells to the lethal effect of bioreductive drugs. Carcinogenesis 32 10190555
2016 Downregulation of GABAA Receptor Recycling Mediated by HAP1 Contributes to Neuronal Death in In Vitro Brain Ischemia. Molecular neurobiology 31 26732589
1998 HAP1-huntingtin interactions do not contribute to the molecular pathology in Huntington's disease transgenic mice. FEBS letters 31 9599014
2007 Regulation of intracellular HAP1 trafficking. Journal of neuroscience research 30 17474105
2003 Structural environment dictates the biological significance of heme-responsive motifs and the role of Hsp90 in the activation of the heme activator protein Hap1. Molecular and cellular biology 30 12897155
1999 The yeast heme-responsive transcriptional activator Hap1 is a preexisting dimer in the absence of heme. The Journal of biological chemistry 30 10428861
2017 Huntingtin-associated protein-1 (HAP1) regulates endocytosis and interacts with multiple trafficking-related proteins. Cellular signalling 29 28259758
2002 The molecular chaperone Hsp90 mediates heme activation of the yeast transcriptional activator Hap1. The Journal of biological chemistry 28 11751848
1999 Regulation of the Saccharomyces cerevisiae DLD1 gene encoding the mitochondrial protein D-lactate ferricytochrome c oxidoreductase by HAP1 and HAP2/3/4/5. Molecular & general genetics : MGG 28 10628845
2017 DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome. Proceedings of the National Academy of Sciences of the United States of America 26 28137862
2017 HAP1 Is Required for Endocytosis and Signalling of BDNF and Its Receptors in Neurons. Molecular neurobiology 25 28083816
2015 Postnatal loss of hap1 reduces hippocampal neurogenesis and causes adult depressive-like behavior in mice. PLoS genetics 25 25875952
2005 8-OxoA inhibits the incision of an AP site by the DNA glycosylases Fpg, Nth and the AP endonuclease HAP1. Radiation research 24 15606310
1999 Structure of HAP1-18-DNA implicates direct allosteric effect of protein-DNA interactions on transcriptional activation. Nature structural biology 24 9886287
1994 Functional analysis of the zinc cluster domain of the CYP1 (HAP1) complex regulator in heme-sufficient and heme-deficient yeast cells. Molecular & general genetics : MGG 24 8152420
2023 HAP1, a new revolutionary cell model for gene editing using CRISPR-Cas9. Frontiers in cell and developmental biology 23 36936678
2007 HAP1 can sequester a subset of TBP in cytoplasmic inclusions via specific interaction with the conserved TBP(CORE). BMC molecular biology 23 17868456
2010 Brainstem Hap1-Ahi1 is involved in insulin-mediated feeding control. FEBS letters 22 21146532
1996 1H, 15N resonance assignment and three-dimensional structure of CYP1 (HAP1) DNA-binding domain. Journal of molecular biology 22 8683583
2019 HAP1 is an in vivo UBE3A target that augments autophagy in a mouse model of Angelman syndrome. Neurobiology of disease 21 31445164
1992 The human gene for apurinic/apyrimidinic endonuclease (HAP1): sequence and localization to chromosome 14 band q12. Nucleic acids research 21 1380694
2012 Characterization of the "sporadically lurking HAP1-immunoreactive (SLH) cells" in the hippocampus, with special reference to the expression of steroid receptors, GABA, and progenitor cell markers. Neuroscience 20 22421101
2009 The effect of bacteriophages T4 and HAP1 on in vitro melanoma migration. BMC microbiology 19 19154575
1998 Gene structure and map location of the murine homolog of the Huntington-associated protein, Hap1. Mammalian genome : official journal of the International Mammalian Genome Society 19 9657855
1995 Multiple domains mediate heme control of the yeast activator HAP1. Molecular & general genetics : MGG 19 7651346
2018 Distribution of HAP1-immunoreactive Cells in the Retrosplenial-retrohippocampal Area of Adult Rat Brain and Its Application to a Refined Neuroanatomical Understanding of the Region. Neuroscience 18 30367943
1994 A novel allele of HAP1 causes uninducible expression of HEM13 in Saccharomyces cerevisiae. Genetics 18 8005437
1990 Internal deletions in the yeast transcriptional activator HAP1 have opposite effects at two sequence elements. Proceedings of the National Academy of Sciences of the United States of America 18 2162046
2013 A novel Hap1-Tsc1 interaction regulates neuronal mTORC1 signaling and morphogenesis in the brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 24227713
2009 Synthetic peptide issued from Hap1/LipL32 for new early serodiagnosis of human leptospirosis. Comparative immunology, microbiology and infectious diseases 16 19307019

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