Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM5I26B)

• DOT Name: Small RNA 2'-O-methyltransferase (HENMT1)
• Synonyms: EC 2.1.1.386; HEN1 methyltransferase homolog 1
• Gene Name: HENMT1
• Related Disease:
  Klinefelter syndrome
  Neuroblastoma
  T-cell acute lymphoblastic leukaemia
• UniProt ID: HENMT_HUMAN
• PDB ID: 4XCX; 5WY0
• EC Number: 2.1.1.386
• Pfam ID: PF13489
• Sequence:
  MEENNLQCSSVVDGNFEEVPRETAIQFKPPLYRQRYQFVKNLVDQHEPKKVADLGCGDTS
  LLRLLKVNPCIELLVGVDINEDKLRWRGDSLAPFLGDFLKPRDLNLTITLYHGSVVERDS
  RLLGFDLITCIELIEHLDSGDLARFPEVVFGYLSPSMIVISTPNSEFNPLFPSVTLRDSD
  HKFEWTRMEFQTWALYVANRYDYSVEFTGVGEPPAGAENVGYCTQIGIFRKNGGKATESC
  LSEQHDQHVYKAVFTTSYPSLQQERFFKLVLVNEVSQQVESLRVSHLPRRKEQAGERGDK
  PKDIGGSKAPVPCFGPVFTEVEKAKIENSPTPFCVGDKFFVPLQRLLAYPKLNRLCANEE
  MMRSVIADSIPLSSDGSAVVADLRNYFDEQFEF
• Function: Methyltransferase that adds a 2'-O-methyl group at the 3'-end of piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence elements. This probably protects the 3'-end of piRNAs from uridylation activity and subsequent degradation. Stabilization of piRNAs is essential for gametogenesis.
• Reactome Pathway: PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Klinefelter syndrome	DISOUI7W	Strong	Genetic Variation	[1]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[2]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Small RNA 2'-O-methyltransferase (HENMT1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Small RNA 2'-O-methyltransferase (HENMT1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Small RNA 2'-O-methyltransferase (HENMT1).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Small RNA 2'-O-methyltransferase (HENMT1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Small RNA 2'-O-methyltransferase (HENMT1).	[9]

2 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 Small RNA 2'-O-methyltransferase (HENMT1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Small RNA 2'-O-methyltransferase (HENMT1).	[8]

References

• [1] Genome-wide site-specific differential methylation in the blood of individuals with Klinefelter syndrome.Mol Reprod Dev. 2015 May;82(5):377-86. doi: 10.1002/mrd.22483. Epub 2015 Apr 30.
• [2] HEN1 and HEN2: a subgroup of basic helix-loop-helix genes that are coexpressed in a human neuroblastoma.Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8492-6. doi: 10.1073/pnas.89.18.8492.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] 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.
• [9] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.