Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFMR3TF)

• DOT Name: YTH domain-containing protein 1
• Synonyms: Splicing factor YT521; YT521-B
• Gene Name: YTHDC1
• Related Disease: Autism spectrum disorder
• UniProt ID: YTDC1_HUMAN
• PDB ID: 2YUD ; 4R3H ; 4R3I ; 6RT4 ; 6RT5 ; 6RT6 ; 6RT7 ; 6SYZ ; 6SZ1 ; 6SZ2 ; 6SZ3 ; 6SZL ; 6SZN ; 6SZR ; 6SZT ; 6SZX ; 6SZY ; 6T01 ; 6T02 ; 6T03 ; 6T04 ; 6T05 ; 6T06 ; 6T07 ; 6T08 ; 6T09 ; 6T0A ; 6T0C ; 6T0D ; 6T0O ; 6T0X ; 6T0Z ; 6T10 ; 6T11 ; 6T12 ; 6WE8 ; 6WE9 ; 6WEA ; 6YKE ; 6YKI ; 6YKJ ; 6YKZ ; 6YL0 ; 6YL8 ; 6YL9 ; 6YM2 ; 6YM8 ; 6YNI ; 6YNJ ; 6YNK ; 6YNL ; 6YNM ; 6YNN ; 6YNO ; 6YNP ; 6YOQ ; 6ZCM ; 6ZCN ; 6ZD9 ; 7L4X ; 7L4Y ; 7P87 ; 7P88 ; 7P8A ; 7P8B ; 7P8F ; 7PJ7 ; 7PJ8 ; 7PJ9 ; 7PJA ; 7PJB ; 7PJP ; 7PJQ ; 7PO6 ; 8Q2Q ; 8Q2R ; 8Q2S ; 8Q2T ; 8Q2U ; 8Q2V ; 8Q2W ; 8Q2X ; 8Q2Y ; 8Q31 ; 8Q32 ; 8Q33 ; 8Q35 ; 8Q37 ; 8Q38 ; 8Q39 ; 8Q3A ; 8Q3G ; 8Q4M ; 8Q4N ; 8Q4P ; 8Q4Q ; 8Q4R ; 8Q4T ; 8Q4U ; 8Q4V ; 8Q4W
• Pfam ID: PF04146
• Sequence:
  MAADSREEKDGELNVLDDILTEVPEQDDELYNPESEQDKNEKKGSKRKSDRMESTDTKRQ
  KPSVHSRQLVSKPLSSSVSNNKRIVSTKGKSATEYKNEEYQRSERNKRLDADRKIRLSSS
  ASREPYKNQPEKTCVRKRDPERRAKSPTPDGSERIGLEVDRRASRSSQSSKEEVNSEEYG
  SDHETGSSGSSDEQGNNTENEEEGVEEDVEEDEEVEEDAEEDEEVDEDGEEEEEEEEEEE
  EEEEEEEEEYEQDERDQKEEGNDYDTRSEASDSGSESVSFTDGSVRSGSGTDGSDEKKKE
  RKRARGISPIVFDRSGSSASESYAGSEKKHEKLSSSVRAVRKDQTSKLKYVLQDARFFLI
  KSNNHENVSLAKAKGVWSTLPVNEKKLNLAFRSARSVILIFSVRESGKFQGFARLSSESH
  HGGSPIHWVLPAGMSAKMLGGVFKIDWICRRELPFTKSAHLTNPWNEHKPVKIGRDGQEI
  ELECGTQLCLLFPPDESIDLYQVIHKMRHKRRMHSQPRSRGRPSRREPVRDVGRRRPEDY
  DIHNSRKKPRIDYPPEFHQRPGYLKDPRYQEVDRRFSGVRRDVFLNGSYNDYVREFHNMG
  PPPPWQGMPPYPGMEQPPHHPYYQHHAPPPQAHPPYSGHHPVPHEARYRDKRVHDYDMRV
  DDFLRRTQAVVSGRRSRPRERDRERERDRPRDNRRDRERDRGRDRERERERLCDRDRDRG
  ERGRYRR
• Function: Regulator of alternative splicing that specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs. M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in the efficiency of mRNA splicing, processing and stability. Acts as a key regulator of exon-inclusion or exon-skipping during alternative splicing via interaction with mRNA splicing factors SRSF3 and SRSF10. Specifically binds m6A-containing mRNAs and promotes recruitment of SRSF3 to its mRNA-binding elements adjacent to m6A sites, leading to exon-inclusion during alternative splicing. In contrast, interaction with SRSF3 prevents interaction with SRSF10, a splicing factor that promotes exon skipping: this prevents SRSF10 from binding to its mRNA-binding sites close to m6A-containing regions, leading to inhibit exon skipping during alternative splicing. May also regulate alternative splice site selection. Also involved in nuclear export of m6A-containing mRNAs via interaction with SRSF3: interaction with SRSF3 facilitates m6A-containing mRNA-binding to both SRSF3 and NXF1, promoting mRNA nuclear export. Involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts, probably by binding m6A-containing MAT2A mRNAs. Also recognizes and binds m6A on other RNA molecules. Involved in random X inactivation mediated by Xist RNA: recognizes and binds m6A-containing Xist and promotes transcription repression activity of Xist. Also recognizes and binds m6A-containing single-stranded DNA. Involved in germline development: required for spermatogonial development in males and oocyte growth and maturation in females, probably via its role in alternative splicing.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[1]

9 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 YTH domain-containing protein 1.	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of YTH domain-containing protein 1.	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of YTH domain-containing protein 1.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of YTH domain-containing protein 1.	[5]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of YTH domain-containing protein 1.	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of YTH domain-containing protein 1.	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of YTH domain-containing protein 1.	[8]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of YTH domain-containing protein 1.	[11]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of YTH domain-containing protein 1.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of YTH domain-containing protein 1.	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of YTH domain-containing protein 1.	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of YTH domain-containing protein 1.	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of YTH domain-containing protein 1.	[10]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.