Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6TPQMH)

DOT Name N6-adenosine-methyltransferase non-catalytic subunit (METTL14)
Synonyms Methyltransferase-like protein 14; hMETTL14
Gene Name METTL14
Related Disease
Neoplasm ( )
Acute lymphocytic leukaemia ( )
Acute myelogenous leukaemia ( )
Advanced cancer ( )
Childhood acute lymphoblastic leukemia ( )
Endometrial cancer ( )
Endometrial carcinoma ( )
leukaemia ( )
Leukemia ( )
Lung squamous cell carcinoma ( )
Obesity ( )
Colorectal carcinoma ( )
Hepatocellular carcinoma ( )
Metastatic malignant neoplasm ( )
Gastric cancer ( )
Stomach cancer ( )
UniProt ID
MET14_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
5IL0 ; 5IL1 ; 5IL2 ; 5K7M ; 5K7U ; 5K7W ; 5L6D ; 5L6E ; 5TEY ; 6TTP ; 6TTT ; 6TTV ; 6TTW ; 6TTX ; 6TU1 ; 6Y4G ; 7ACD ; 7NHG ; 7NHH ; 7NHI ; 7NHJ ; 7NHV ; 7NI7 ; 7NI8 ; 7NI9 ; 7NIA ; 7NID ; 7O08 ; 7O09 ; 7O0L ; 7O0M ; 7O0P ; 7O0Q ; 7O0R ; 7O27 ; 7O28 ; 7O29 ; 7O2E ; 7O2F ; 7O2H ; 7O2I ; 7O2X ; 7OED ; 7OEE ; 7OEF ; 7OEG ; 7OEH ; 7OEI ; 7OEJ ; 7OEK ; 7OEL ; 7OEM ; 7OQL ; 7OQO ; 7OQP ; 7RX6 ; 7RX7 ; 7RX8 ; 8BN8
Pfam ID
PF05063
Sequence
MDSRLQEIRERQKLRRQLLAQQLGAESADSIGAVLNSKDEQREIAETRETCRASYDTSAP
NAKRKYLDEGETDEDKMEEYKDELEMQQDEENLPYEEEIYKDSSTFLKGTQSLNPHNDYC
QHFVDTGHRPQNFIRDVGLADRFEEYPKLRELIRLKDELIAKSNTPPMYLQADIEAFDIR
ELTPKFDVILLEPPLEEYYRETGITANEKCWTWDDIMKLEIDEIAAPRSFIFLWCGSGEG
LDLGRVCLRKWGYRRCEDICWIKTNKNNPGKTKTLDPKAVFQRTKEHCLMGIKGTVKRST
DGDFIHANVDIDLIITEEPEIGNIEKPVEIFHIIEHFCLGRRRLHLFGRDSTIRPGWLTV
GPTLTNSNYNAETYASYFSAPNSYLTGCTEEIERLRPKSPPPKSKSDRGGGAPRGGGRGG
TSAGRGRERNRSNFRGERGGFRGGRGGAHRGGFPPR
Function
The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) position of some mRNAs and regulates the circadian clock, differentiation of embryonic stem cells and cortical neurogenesis. In the heterodimer formed with METTL3, METTL14 constitutes the RNA-binding scaffold that recognizes the substrate rather than the catalytic core. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability and processing. M6A acts as a key regulator of mRNA stability by promoting mRNA destabilization and degradation. In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization. M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis. M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells.
Reactome Pathway
Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203 )

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Neoplasm DISZKGEW Definitive Biomarker [1]
Acute lymphocytic leukaemia DISPX75S Strong Biomarker [2]
Acute myelogenous leukaemia DISCSPTN Strong Biomarker [3]
Advanced cancer DISAT1Z9 Strong Biomarker [4]
Childhood acute lymphoblastic leukemia DISJ5D6U Strong Biomarker [2]
Endometrial cancer DISW0LMR Strong Genetic Variation [5]
Endometrial carcinoma DISXR5CY Strong Genetic Variation [5]
leukaemia DISS7D1V Strong Biomarker [3]
Leukemia DISNAKFL Strong Biomarker [3]
Lung squamous cell carcinoma DISXPIBD Strong Biomarker [6]
Obesity DIS47Y1K Strong Biomarker [7]
Colorectal carcinoma DIS5PYL0 moderate Biomarker [8]
Hepatocellular carcinoma DIS0J828 moderate Biomarker [9]
Metastatic malignant neoplasm DIS86UK6 moderate Biomarker [9]
Gastric cancer DISXGOUK Limited Biomarker [10]
Stomach cancer DISKIJSX Limited Biomarker [10]
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⏷ Show the Full List of 16 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
3 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 N6-adenosine-methyltransferase non-catalytic subunit (METTL14). [11]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of N6-adenosine-methyltransferase non-catalytic subunit (METTL14). [16]
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of N6-adenosine-methyltransferase non-catalytic subunit (METTL14). [17]
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4 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of N6-adenosine-methyltransferase non-catalytic subunit (METTL14). [12]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of N6-adenosine-methyltransferase non-catalytic subunit (METTL14). [13]
Arsenic DMTL2Y1 Approved Arsenic increases the expression of N6-adenosine-methyltransferase non-catalytic subunit (METTL14). [14]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of N6-adenosine-methyltransferase non-catalytic subunit (METTL14). [15]
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References

1 Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N(6)-methyladenosine of Notch1.Mol Cancer. 2019 Nov 25;18(1):168. doi: 10.1186/s12943-019-1084-1.
2 The study of METTL3 and METTL14 expressions in childhood ETV6/RUNX1-positive acute lymphoblastic leukemia.Mol Genet Genomic Med. 2019 Oct;7(10):e00933. doi: 10.1002/mgg3.933. Epub 2019 Aug 20.
3 METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification.Cell Stem Cell. 2018 Feb 1;22(2):191-205.e9. doi: 10.1016/j.stem.2017.11.016. Epub 2017 Dec 28.
4 Changes of N6-methyladenosine modulators promote breast cancer progression.BMC Cancer. 2019 Apr 5;19(1):326. doi: 10.1186/s12885-019-5538-z.
5 m(6)A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer.Nat Cell Biol. 2018 Sep;20(9):1074-1083. doi: 10.1038/s41556-018-0174-4. Epub 2018 Aug 27.
6 m(6)A demethylase FTO facilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression.Biochem Biophys Res Commun. 2018 Aug 25;502(4):456-464. doi: 10.1016/j.bbrc.2018.05.175. Epub 2018 Jun 2.
7 The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis.Mol Cell Biol. 2018 Jul 30;38(16):e00116-18. doi: 10.1128/MCB.00116-18. Print 2018 Aug 15.
8 RETRACTED: METTL14 Suppresses CRC Progression via Regulating N6-Methyladenosine-Dependent Primary miR-375 Processing.Mol Ther. 2020 Feb 5;28(2):599-612. doi: 10.1016/j.ymthe.2019.11.016. Epub 2019 Nov 20.
9 METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N(6) -methyladenosine-dependent primary MicroRNA processing.Hepatology. 2017 Feb;65(2):529-543. doi: 10.1002/hep.28885. Epub 2016 Dec 24.
10 Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K-Akt signaling in gastric cancer.Cancer Med. 2019 Aug;8(10):4766-4781. doi: 10.1002/cam4.2360. Epub 2019 Jun 26.
11 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.
12 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
13 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.
14 Role of N6-methyladenosine RNA modification in the imbalanced inflammatory homeostasis of arsenic-induced skin lesions. Environ Toxicol. 2022 Aug;37(8):1831-1839. doi: 10.1002/tox.23530. Epub 2022 Apr 1.
15 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
16 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.
17 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.