Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMGP4J7)

• DOT Name: Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2)
• Synonyms: hnRNP H2; FTP-3; Heterogeneous nuclear ribonucleoprotein H'; hnRNP H'
• Gene Name: HNRNPH2
• Related Disease:
  Advanced cancer
  Amyotrophic lateral sclerosis
  Heroin dependence
  Intellectual disability, X-linked, syndromic, Bain type
  Mental disorder
  Neurodevelopmental disorder
  Congenital myasthenic syndrome
  Frontotemporal dementia
  Intellectual disability
  Myotonic dystrophy type 1
• UniProt ID: HNRH2_HUMAN
• PDB ID: 1WEZ; 1WG5; 6DG1; 8SGH
• Pfam ID: PF00076 ; PF08080
• Sequence:
  MMLSTEGREGFVVKVRGLPWSCSADEVMRFFSDCKIQNGTSGIRFIYTREGRPSGEAFVE
  LESEEEVKLALKKDRETMGHRYVEVFKSNSVEMDWVLKHTGPNSPDTANDGFVRLRGLPF
  GCSKEEIVQFFSGLEIVPNGMTLPVDFQGRSTGEAFVQFASQEIAEKALKKHKERIGHRY
  IEIFKSSRAEVRTHYDPPRKLMAMQRPGPYDRPGAGRGYNSIGRGAGFERMRRGAYGGGY
  GGYDDYGGYNDGYGFGSDRFGRDLNYCFSGMSDHRYGDGGSSFQSTTGHCVHMRGLPYRA
  TENDIYNFFSPLNPMRVHIEIGPDGRVTGEADVEFATHEDAVAAMAKDKANMQHRYVELF
  LNSTAGTSGGAYDHSYVELFLNSTAGASGGAYGSQMMGGMGLSNQSSYGGPASQQLSGGY
  GGGYGGQSSMSGYDQVLQENSSDYQSNLA
• Function: This protein is a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes which provide the substrate for the processing events that pre-mRNAs undergo before becoming functional, translatable mRNAs in the cytoplasm. Binds poly(RG).
• Tissue Specificity: Expressed ubiquitously.
• Reactome Pathway:
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[2]
Heroin dependence	DISQ1H57	Strong	Genetic Variation	[3]
Intellectual disability, X-linked, syndromic, Bain type	DISO1F6U	Strong	X-linked	[4]
Mental disorder	DIS3J5R8	Strong	Biomarker	[5]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[4]
Congenital myasthenic syndrome	DISJLG2T	moderate	Biomarker	[6]
Frontotemporal dementia	DISKYHXL	moderate	Biomarker	[2]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[7]
Myotonic dystrophy type 1	DISJC0OX	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[13]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[15]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[20]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[21]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[22]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[23]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2).	[19]

References

• [1] Decoding a cancer-relevant splicing decision in the RON proto-oncogene using high-throughput mutagenesis.Nat Commun. 2018 Aug 17;9(1):3315. doi: 10.1038/s41467-018-05748-7.
• [2] The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains.Elife. 2016 Sep 13;5:e17820. doi: 10.7554/eLife.17820.
• [3] A heroin addiction severity-associated intronic single nucleotide polymorphism modulates alternative pre-mRNA splicing of the opioid receptor gene OPRM1 via hnRNPH interactions.J Neurosci. 2014 Aug 13;34(33):11048-66. doi: 10.1523/JNEUROSCI.3986-13.2014.
• [4] Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females. Am J Hum Genet. 2016 Sep 1;99(3):728-734. doi: 10.1016/j.ajhg.2016.06.028. Epub 2016 Aug 18.
• [5] Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation. Clin Genet. 2018 Oct;94(3-4):381-385. doi: 10.1111/cge.13410. Epub 2018 Aug 2.
• [6] SRSF1 and hnRNP H antagonistically regulate splicing of COLQ exon 16 in a congenital myasthenic syndrome.Sci Rep. 2015 Aug 18;5:13208. doi: 10.1038/srep13208.
• [7] Bain type of X-linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2.Am J Med Genet A. 2020 Jan;182(1):183-188. doi: 10.1002/ajmg.a.61388. Epub 2019 Oct 31.
• [8] Interaction of muscleblind, CUG-BP1 and hnRNP H proteins in DM1-associated aberrant IR splicing.EMBO J. 2006 Sep 20;25(18):4271-83. doi: 10.1038/sj.emboj.7601296. Epub 2006 Aug 31.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Synergistic effects of retinoic acid and tamoxifen on human breast cancer cells: proteomic characterization. Exp Cell Res. 2007 Jan 15;313(2):357-68. doi: 10.1016/j.yexcr.2006.10.016. Epub 2006 Oct 25.
• [11] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [14] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [17] 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.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [21] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [22] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [23] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [24] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.