Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT061H4E)

• DOT Name: N(6)-adenine-specific methyltransferase METTL4 (METTL4)
• Synonyms: Methyltransferase-like protein 4; N(6)-adenine-specific DNA methyltransferase METTL4; EC 2.1.1.72; snRNA (2'-O-methyladenosine-N(6)-)-methyltransferase METTL4; EC 2.1.1.-
• Gene Name: METTL4
• Related Disease:
  Melanoma
  Neoplasm
• UniProt ID: METL4_HUMAN
• EC Number: 2.1.1.-; 2.1.1.72
• Pfam ID: PF05063
• Sequence:
  MSVVHQLSAGWLLDHLSFINKINYQLHQHHEPCCRKKEFTTSVHFESLQMDSVSSSGVCA
  AFIASDSSTKPENDDGGNYEMFTRKFVFRPELFDVTKPYITPAVHKECQQSNEKEDLMNG
  VKKEISISIIGKKRKRCVVFNQGELDAMEYHTKIRELILDGSLQLIQEGLKSGFLYPLFE
  KQDKGSKPITLPLDACSLSELCEMAKHLPSLNEMEHQTLQLVEEDTSVTEQDLFLRVVEN
  NSSFTKVITLMGQKYLLPPKSSFLLSDISCMQPLLNYRKTFDVIVIDPPWQNKSVKRSNR
  YSYLSPLQIQQIPIPKLAAPNCLLVTWVTNRQKHLRFIKEELYPSWSVEVVAEWHWVKIT
  NSGEFVFPLDSPHKKPYEGLILGRVQEKTALPLRNADVNVLPIPDHKLIVSVPCTLHSHK
  PPLAEVLKDYIKPDGEYLELFARNLQPGWTSWGNEVLKFQHVDYFIAVESGS
• Function: N(6)-adenine-specific methyltransferase that can methylate both RNAs and DNA. Acts as a N(6)-adenine-specific RNA methyltransferase by catalyzing formation of N6,2'-O-dimethyladenosine (m6A(m)) on internal positions of U2 small nuclear RNA (snRNA): methylates the 6th position of adenine residues with a pre-deposited 2'-O-methylation. Internal m6A(m) methylation of snRNAs regulates RNA splicing. Also able to act as a N(6)-adenine-specific DNA methyltransferase by mediating methylation of DNA on the 6th position of adenine (N(6)-methyladenosine). The existence of N(6)-methyladenosine (m6A) on DNA is however unclear in mammals, and additional evidences are required to confirm the role of the N(6)-adenine-specific DNA methyltransferase activity of METTL4 in vivo. Acts as a regulator of mitochondrial transcript levels and mitochondrial DNA (mtDNA) copy number by mediating mtDNA N(6)-methylation: m6A on mtDNA reduces transcription by repressing TFAM DNA-binding and bending. N(6)-methyladenosine deposition by METTL4 regulates Polycomb silencing by triggering ubiquitination and degradation of sensor proteins ASXL1 and MPND, leading to inactivation of the PR-DUB complex and subsequent preservation of Polycomb silencing.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of N(6)-adenine-specific methyltransferase METTL4 (METTL4).	[3]

6 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 N(6)-adenine-specific methyltransferase METTL4 (METTL4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of N(6)-adenine-specific methyltransferase METTL4 (METTL4).	[5]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of N(6)-adenine-specific methyltransferase METTL4 (METTL4).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of N(6)-adenine-specific methyltransferase METTL4 (METTL4).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of N(6)-adenine-specific methyltransferase METTL4 (METTL4).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of N(6)-adenine-specific methyltransferase METTL4 (METTL4).	[9]

References

• [1] Dissecting the role of RNA modification regulatory proteins in melanoma.Oncotarget. 2019 Jun 4;10(38):3745-3759. eCollection 2019 Jun 4.
• [2] The Prognostic Value of m6A RNA Methylation Regulators in Colon Adenocarcinoma.Med Sci Monit. 2019 Dec 11;25:9435-9445. doi: 10.12659/MSM.920381.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis. Cell Biol Toxicol. 2023 Jun;39(3):1015-1035. doi: 10.1007/s10565-021-09660-7. Epub 2021 Oct 14.
• [6] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [7] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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.