Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZK4FU5)

• DOT Name: H/ACA ribonucleoprotein complex subunit 2 (NHP2)
• Synonyms: Nucleolar protein family A member 2; snoRNP protein NHP2
• Gene Name: NHP2
• Related Disease:
  Dyskeratosis congenita, autosomal recessive 2
  Hoyeraal-Hreidarsson syndrome
  Lung neoplasm
  Premature aging syndrome
  Dyskeratosis congenita
• UniProt ID: NHP2_HUMAN
• PDB ID: 7BGB; 7TRC; 7V9A
• Pfam ID: PF01248
• Sequence:
  MTKIKADPDGPEAQAEACSGERTYQELLVNQNPIAQPLASRRLTRKLYKCIKKAVKQKQI
  RRGVKEVQKFVNKGEKGIMVLAGDTLPIEVYCHLPVMCEDRNLPYVYIPSKTDLGAAAGS
  KRPTCVIMVKPHEEYQEAYDECLEEVQSLPLPL
• Function: Required for ribosome biogenesis and telomere maintenance. Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA. This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1. Each rRNA can contain up to 100 pseudouridine ('psi') residues, which may serve to stabilize the conformation of rRNAs. May also be required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme.
• Tissue Specificity: Expressed in brain, colon, heart, kidney, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine, spleen, testis and thymus. Also expressed at lower levels in the liver.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)
• Reactome Pathway:
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)
  Telomere Extension By Telomerase (R-HSA-171319)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dyskeratosis congenita, autosomal recessive 2	DISM1J6X	Strong	Autosomal recessive	[1]
Hoyeraal-Hreidarsson syndrome	DISAUR8F	Strong	Biomarker	[2]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[3]
Premature aging syndrome	DIS51AGT	Strong	Genetic Variation	[1]
Dyskeratosis congenita	DISSXV0K	Supportive	Autosomal dominant	[4]

7 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 H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[13]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of H/ACA ribonucleoprotein complex subunit 2 (NHP2).	[11]

References

• [1] Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8073-8. doi: 10.1073/pnas.0800042105. Epub 2008 Jun 3.
• [2] Effects of dyskeratosis congenita mutations in dyskerin, NHP2 and NOP10 on assembly of H/ACA pre-RNPs.Hum Mol Genet. 2010 Mar 1;19(5):825-36. doi: 10.1093/hmg/ddp551. Epub 2009 Dec 15.
• [3] [The NOLA2 and RPS3A genes as highly informative markers for human squamous cell lung cancer].Bioorg Khim. 2005 Mar-Apr;31(2):195-9. doi: 10.1007/s11171-005-0024-6.
• [4] Dyskeratosis Congenita and Related Telomere Biology Disorders. 2009 Nov 12 [updated 2023 Jan 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.