Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT99VP8Y)

• DOT Name: RNA N6-adenosine-methyltransferase METTL16 (METTL16)
• Synonyms: Methyltransferase 10 domain-containing protein; Methyltransferase-like protein 16; N6-adenosine-methyltransferase METTL16; EC 2.1.1.348; U6 small nuclear RNA (adenine-(43)-N(6))-methyltransferase; EC 2.1.1.346
• Gene Name: METTL16
• Related Disease:
  Advanced cancer
  Colon cancer
  Colorectal carcinoma
• UniProt ID: MET16_HUMAN
• PDB ID: 2H00; 6B91; 6B92; 6DU4; 6DU5; 6GFK; 6GFN; 6GT5; 6M1U
• EC Number: 2.1.1.346; 2.1.1.348
• Pfam ID: PF05971
• Sequence:
  MALSKSMHARNRYKDKPPDFAYLASKYPDFKQHVQINLNGRVSLNFKDPEAVRALTCTLL
  REDFGLSIDIPLERLIPTVPLRLNYIHWVEDLIGHQDSDKSTLRRGIDIGTGASCIYPLL
  GATLNGWYFLATEVDDMCFNYAKKNVEQNNLSDLIKVVKVPQKTLLMDALKEESEIIYDF
  CMCNPPFFANQLEAKGVNSRNPRRPPPSSVNTGGITEIMAEGGELEFVKRIIHDSLQLKK
  RLRWYSCMLGKKCSLAPLKEELRIQGVPKVTYTEFCQGRTMRWALAWSFYDDVTVPSPPS
  KRRKLEKPRKPITFVVLASVMKELSLKASPLRSETAEGIVVVTTWIEKILTDLKVQHKRV
  PCGKEEVSLFLTAIENSWIHLRRKKRERVRQLREVPRAPEDVIQALEEKKPTPKESGNSQ
  ELARGPQERTPCGPALREGEAAAVEGPCPSQESLSQEENPEPTEDERSEEKGGVEVLESC
  QGSSNGAQDQEASEQFGSPVAERGKRLPGVAGQYLFKCLINVKKEVDDALVEMHWVEGQN
  RDLMNQLCTYIRNQIFRLVAVN
• Function: RNA N6-methyltransferase that methylates adenosine residues at the N(6) position of a subset of RNAs and is involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts. Able to N6-methylate a subset of mRNAs and U6 small nuclear RNAs (U6 snRNAs). In contrast to the METTL3-METTL14 heterodimer, only able to methylate a limited number of RNAs: requires both a 5'UACAGAGAA-3' nonamer sequence and a specific RNA structure. Plays a key role in S-adenosyl-L-methionine homeostasis by mediating N6-methylation of MAT2A mRNAs, altering splicing of MAT2A transcripts: in presence of S-adenosyl-L-methionine, binds the 3'-UTR region of MAT2A mRNA and specifically N6-methylates the first hairpin of MAT2A mRNA, preventing recognition of their 3'-splice site by U2AF1/U2AF35, thereby inhibiting splicing and protein production of S-adenosylmethionine synthase. In S-adenosyl-L-methionine-limiting conditions, binds the 3'-UTR region of MAT2A mRNA but stalls due to the lack of a methyl donor, preventing N6-methylation and promoting expression of MAT2A. In addition to mRNAs, also able to mediate N6-methylation of U6 small nuclear RNA (U6 snRNA): specifically N6-methylates adenine in position 43 of U6 snRNAs. Also able to bind various lncRNAs, such as 7SK snRNA (7SK RNA) or 7SL RNA. Specifically binds the 3'-end of the MALAT1 long non-coding RNA.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]

6 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 RNA N6-adenosine-methyltransferase METTL16 (METTL16).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RNA N6-adenosine-methyltransferase METTL16 (METTL16).	[3]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of RNA N6-adenosine-methyltransferase METTL16 (METTL16).	[4]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of RNA N6-adenosine-methyltransferase METTL16 (METTL16).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of RNA N6-adenosine-methyltransferase METTL16 (METTL16).	[6]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of RNA N6-adenosine-methyltransferase METTL16 (METTL16).	[7]

References

• [1] Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers.Pathol Oncol Res. 2018 Jul;24(3):617-622. doi: 10.1007/s12253-017-0287-2. Epub 2017 Aug 12.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [5] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [6] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [7] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.