Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6SG0JQ)

• DOT Name: Huntingtin-associated protein 1 (HAP1)
• Synonyms: HAP-1; Neuroan 1
• Gene Name: HAP1
• Related Disease:
  Acute lymphocytic leukaemia
  Angelman syndrome
  Childhood acute lymphoblastic leukemia
  Adult respiratory distress syndrome
  Alzheimer disease
  Breast neoplasm
  Cerebral infarction
  Dengue
  Duchenne muscular dystrophy
  Haemophilia A
  Hemophilia
  Huntington disease
  Hyperinsulinemia
  Joubert syndrome
  Kennedy disease
  Laurin-Sandrow syndrome
  Lung cancer
  Lung carcinoma
  Male infertility
  Mental disorder
  Multiple sclerosis
  Neoplasm
  Nephropathy
  Osteoporosis
  Breast cancer
  Breast carcinoma
  High blood pressure
  Spinocerebellar ataxia type 17
  Transposition of the great arteries
  Primary biliary cholangitis
  Chronic pancreatitis
  Essential hypertension
  Frontotemporal dementia
  Glioma
  Malaria
  Pancreatic cancer
  Parkinsonian disorder
  Periodontitis
  Pick disease
  Subarachnoid hemorrhage
  Temporal lobe epilepsy
• UniProt ID: HAP1_HUMAN
• Pfam ID: PF04849
• Sequence:
  MRPKRLGRCCAGSRLGPGDPAALTCAPSPSASPAPEPSAQPQARGTGQRVGSRATSGSQF
  LSEARTGARPASEAGAKAGARRPSAFSAIQGDVRSMPDNSDAPWTRFVFQGPFGSRATGR
  GTGKAAGIWKTPAAYVGRRPGVSGPERAAFIRELEEALCPNLPPPVKKITQEDVKVMLYL
  LEELLPPVWESVTYGMVLQRERDLNTAARIGQSLVKQNSVLMEENSKLEALLGSAKEEIL
  YLRHQVNLRDELLQLYSDSDEEDEDEEEEEEEKEAEEEQEEEEAEEDLQCAHPCDAPKLI
  SQEALLHQHHCPQLEALQEKLRLLEEENHQLREEASQLDTLEDEEQMLILECVEQFSEAS
  QQMAELSEVLVLRLENYERQQQEVARLQAQVLKLQQRCRMYGAETEKLQKQLASEKEIQM
  QLQEESVWVGSQLQDLREKYMDCGGMLIEMQEEVKTLRQQPPVSTGSATHYPYSVPLETL
  PGFQETLAEELRTSLRRMISDPVYFMERNYEMPRGDTSSLRYDFRYSEDREQVRGFEAEE
  GLMLAADIMRGEDFTPAEEFVPQEELGAAKKVPAEEGVMEEAELVSEETEGWEEVELELD
  EATRMNVVTSALEASGLGPSHLDMNYVLQQLANWQDAHYRRQLRWKMLQKGECPHGALPA
  ASRTSCRSSCR
• Function: Originally identified as neuronal protein that specifically associates with HTT/huntingtin and the binding is enhanced by an expanded polyglutamine repeat within HTT possibly affecting HAP1 interaction properties. Both HTT and HAP1 are involved in intracellular trafficking and HAP1 is proposed to link HTT to motor proteins and/or transport cargos. Seems to play a role in vesicular transport within neurons and axons such as from early endosomes to late endocytic compartments and to promote neurite outgrowth. The vesicular transport function via association with microtubule-dependent transporters can be attenuated by association with mutant HTT. Involved in the axonal transport of BDNF and its activity-dependent secretion; the function seems to involve HTT, DCTN1 and a complex with SORT1. Involved in APP trafficking and seems to facilitate APP anterograde transport and membrane insertion thereby possibly reducing processing into amyloid beta. Involved in delivery of gamma-aminobutyric acid (GABA(A)) receptors to synapses; the function is dependent on kinesin motor protein KIF5 and is disrupted by HTT with expanded polyglutamine repeat. Involved in regulation of autophagosome motility by promoting efficient retrograde axonal transport. Seems to be involved in regulation of membrane receptor recycling and degradation, and respective signal transduction, including GABA(A) receptors, tyrosine kinase receptors, EGFR, IP3 receptor and androgen receptor. Among others suggested to be involved in control of feeding behavior (involving hypothalamic GABA(A) receptors), cerebellar and brainstem development (involving AHI1 and NTRK1/TrkA), postnatal neurogenesis (involving hypothalamic NTRK2/TrkB), and ITPR1/InsP3R1-mediated Ca(2+) release (involving HTT and possibly the effect of mutant HTT). Via association with DCTN1/dynactin p150-glued and HTT/huntingtin involved in cytoplasmic retention of REST in neurons. May be involved in ciliogenesis. Involved in regulation of exocytosis. Seems to be involved in formation of cytoplasmic inclusion bodies (STBs). In case of anomalous expression of TBP, can sequester a subset of TBP into STBs; sequestration is enhanced by an expanded polyglutamine repeat within TBP. HAP1-containing STBs have been proposed to play a protective role against neurodegeneration in Huntigton disease (HD) and spinocerebellar ataxia 17 (SCA17).
• Tissue Specificity: Predominantly expressed in brain. Selectively expressed in neurons.
• KEGG Pathway:
  GABAergic sy.pse (hsa04727)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Definitive	Biomarker	[1]
Angelman syndrome	DIS4QVXO	Definitive	Biomarker	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Definitive	Biomarker	[1]
Adult respiratory distress syndrome	DISIJV47	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[6]
Dengue	DISKH221	Strong	Biomarker	[7]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[8]
Haemophilia A	DIS0RQ2E	Strong	Genetic Variation	[9]
Hemophilia	DIS1S8P6	Strong	Genetic Variation	[9]
Huntington disease	DISQPLA4	Strong	Biomarker	[2]
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[10]
Joubert syndrome	DIS7P5CO	Strong	Genetic Variation	[11]
Kennedy disease	DISXZVM1	Strong	Biomarker	[12]
Laurin-Sandrow syndrome	DISOYBC3	Strong	Genetic Variation	[13]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[14]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[14]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[15]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[16]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Nephropathy	DISXWP4P	Strong	Altered Expression	[10]
Osteoporosis	DISF2JE0	Strong	Biomarker	[18]
Breast cancer	DIS7DPX1	moderate	Biomarker	[19]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[19]
High blood pressure	DISY2OHH	moderate	Biomarker	[20]
Spinocerebellar ataxia type 17	DISJXO7P	moderate	Biomarker	[21]
Transposition of the great arteries	DISPXJ8X	moderate	Genetic Variation	[22]
Primary biliary cholangitis	DIS43E0O	Disputed	Biomarker	[23]
Chronic pancreatitis	DISBUOMJ	Limited	Genetic Variation	[24]
Essential hypertension	DIS7WI98	Limited	Genetic Variation	[25]
Frontotemporal dementia	DISKYHXL	Limited	Genetic Variation	[26]
Glioma	DIS5RPEH	Limited	Altered Expression	[27]
Malaria	DISQ9Y50	Limited	Biomarker	[28]
Pancreatic cancer	DISJC981	Limited	Biomarker	[29]
Parkinsonian disorder	DISHGY45	Limited	Genetic Variation	[26]
Periodontitis	DISI9JOI	Limited	Genetic Variation	[30]
Pick disease	DISP6X50	Limited	Genetic Variation	[26]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Genetic Variation	[31]
Temporal lobe epilepsy	DISNOPXX	Limited	Genetic Variation	[32]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Huntingtin-associated protein 1 (HAP1).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Huntingtin-associated protein 1 (HAP1).	[34]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Huntingtin-associated protein 1 (HAP1).	[35]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Huntingtin-associated protein 1 (HAP1).	[37]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Huntingtin-associated protein 1 (HAP1).	[38]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Huntingtin-associated protein 1 (HAP1).	[39]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Huntingtin-associated protein 1 (HAP1).	[39]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Huntingtin-associated protein 1 (HAP1).	[39]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Huntingtin-associated protein 1 (HAP1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Huntingtin-associated protein 1 (HAP1).	[40]

References

• [1] HAP1 loss confers l-asparaginase resistance in ALL by downregulating the calpain-1-Bid-caspase-3/12 pathway.Blood. 2019 May 16;133(20):2222-2232. doi: 10.1182/blood-2018-12-890236. Epub 2019 Feb 28.
• [2] HAP1 is an in vivo UBE3A target that augments autophagy in a mouse model of Angelman syndrome.Neurobiol Dis. 2019 Dec;132:104585. doi: 10.1016/j.nbd.2019.104585. Epub 2019 Aug 21.
• [3] Genetic polymorphisms of peptidase inhibitor 3 (elafin) are associated with acute respiratory distress syndrome.Am J Respir Cell Mol Biol. 2009 Dec;41(6):696-704. doi: 10.1165/rcmb.2008-0410OC. Epub 2009 Feb 27.
• [4] Long-standing balancing selection in the THBS4 gene: influence on sex-specific brain expression and gray matter volumes in Alzheimer disease.Hum Mutat. 2013 May;34(5):743-53. doi: 10.1002/humu.22301. Epub 2013 Apr 2.
• [5] Huntingtin-associated protein 1: a potential biomarker of breast cancer.Oncol Rep. 2013 May;29(5):1881-7. doi: 10.3892/or.2013.2303. Epub 2013 Feb 22.
• [6] Downregulation of GABA(A) Receptor Recycling Mediated by HAP1 Contributes to Neuronal Death in In Vitro Brain Ischemia.Mol Neurobiol. 2017 Jan;54(1):45-57. doi: 10.1007/s12035-015-9661-9. Epub 2016 Jan 5.
• [7] What Came First-the Virus or the Egg?.Cell. 2017 Feb 23;168(5):755-757. doi: 10.1016/j.cell.2017.02.012.
• [8] Huntingtin-associated protein (HAP1): discrete neuronal localizations in the brain resemble those of neuronal nitric oxide synthase.Proc Natl Acad Sci U S A. 1996 May 14;93(10):4839-44. doi: 10.1073/pnas.93.10.4839.
• [9] Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A.Blood. 2006 Dec 1;108(12):3739-45. doi: 10.1182/blood-2006-05-024711. Epub 2006 Aug 22.
• [10] Age-Related Expression of Human AT1R Variants and Associated Renal Dysfunction in Transgenic Mice.Am J Hypertens. 2018 Oct 15;31(11):1234-1242. doi: 10.1093/ajh/hpy121.
• [11] The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions.J Biol Chem. 2013 May 10;288(19):13676-94. doi: 10.1074/jbc.M112.420786. Epub 2013 Mar 26.
• [12] Immunohistochemical analysis of huntingtin-associated protein 1 in adult rat spinal cord and its regional relationship with androgen receptor.Neuroscience. 2017 Jan 6;340:201-217. doi: 10.1016/j.neuroscience.2016.10.053. Epub 2016 Oct 29.
• [13] Progression of lumbar spinal stenosis is influenced by polymorphism of thrombospondin 2 gene in the Korean population.Eur Spine J. 2014 Jan;23(1):57-63. doi: 10.1007/s00586-013-2866-6. Epub 2013 Jun 27.
• [14] Evaluating the association of polymorphisms in the HAP1 gene with lung cancer risk: a meta-analysis.Tumour Biol. 2014 Nov;35(11):10825-31. doi: 10.1007/s13277-014-2236-y. Epub 2014 Aug 1.
• [15] Androgen receptor gene haplotype is associated with male infertility.Int J Androl. 2008 Aug;31(4):395-402. doi: 10.1111/j.1365-2605.2007.00782.x.
• [16] Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer's Disease Model Cells.Mol Neurobiol. 2019 Nov;56(11):7572-7582. doi: 10.1007/s12035-019-1587-1. Epub 2019 May 7.
• [17] IL7R expression and upregulation by IFN in dendritic cell subsets is haplotype-dependent.PLoS One. 2013 Oct 16;8(10):e77508. doi: 10.1371/journal.pone.0077508. eCollection 2013.
• [18] Effect of hydroxyapatite nanoparticles and wedelolactone on osteoblastogenesis from bone marrow mesenchymal stem cells.J Biomed Mater Res A. 2019 Jan;107(1):145-153. doi: 10.1002/jbm.a.36541. Epub 2018 Oct 5.
• [19] HAP1 gene expression is associated with radiosensitivity in breast cancer cells.Biochem Biophys Res Commun. 2015 Jan 2;456(1):162-6. doi: 10.1016/j.bbrc.2014.11.052. Epub 2014 Nov 22.
• [20] A polymorphism in intron I of the human angiotensinogen gene (hAGT) affects binding by HNF3 and hAGT expression and increases blood pressure in mice.J Biol Chem. 2019 Aug 2;294(31):11829-11839. doi: 10.1074/jbc.RA119.007715. Epub 2019 Jun 14.
• [21] HAP1 can sequester a subset of TBP in cytoplasmic inclusions via specific interaction with the conserved TBP(CORE).BMC Mol Biol. 2007 Sep 14;8:76. doi: 10.1186/1471-2199-8-76.
• [22] The INSIG1 gene, not the INSIG2 gene, associated with coronary heart disease: tagSNPs and haplotype-based association study. The Beijing Atherosclerosis Study.Thromb Haemost. 2008 Nov;100(5):886-92.
• [23] Single-nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis.Hepatology. 2008 Sep;48(3):853-62. doi: 10.1002/hep.22382.
• [24] Significance of MUC2 gene methylation detection in pancreatic cancer diagnosis.Pancreatology. 2019 Dec;19(8):1049-1053. doi: 10.1016/j.pan.2019.09.012. Epub 2019 Sep 27.
• [25] Novel genetic variation in exon 28 of FBN1 gene is associated with essential hypertension.Am J Hypertens. 2011 Jun;24(6):687-93. doi: 10.1038/ajh.2011.21. Epub 2011 Feb 17.
• [26] Gene structure and map location of the murine homolog of the Huntington-associated protein, Hap1.Mamm Genome. 1998 Jul;9(7):565-70. doi: 10.1007/s003359900819.
• [27] Expression levels of the DNA repair enzyme HAP1 do not correlate with the radiosensitivities of human or HAP1-transfected rat cell lines.Br J Cancer. 1999 Jun;80(7):940-5. doi: 10.1038/sj.bjc.6690447.
• [28] Transient Expression of Plasmodium berghei MSP8 and HAP2 in the Marine Protozoan Parasite Perkinsus marinus.J Parasitol. 2017 Feb;103(1):118-122. doi: 10.1645/16-88. Epub 2016 Oct 10.
• [29] Expression and Localization of Huntingtin-Associated Protein 1 (HAP1) in the Human Digestive System.Dig Dis Sci. 2019 Jun;64(6):1486-1492. doi: 10.1007/s10620-018-5425-5. Epub 2018 Dec 17.
• [30] The ATC/TTC haplotype in the Interleukin 8 gene in response to Gram-negative bacteria: A pilot study.Arch Oral Biol. 2019 Nov;107:104508. doi: 10.1016/j.archoralbio.2019.104508. Epub 2019 Jul 24.
• [31] Subarachnoid hemorrhage: tests of association with apolipoprotein E and elastin genes.BMC Med Genet. 2007 Jul 31;8:49. doi: 10.1186/1471-2350-8-49.
• [32] Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures.PLoS One. 2010 Sep 16;5(9):e12740. doi: 10.1371/journal.pone.0012740.
• [33] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [34] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [35] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [36] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [37] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [38] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [39] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [40] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.