Details of Drug Off-Target (DOT)

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

• DOT Name: 3'-5' RNA helicase YTHDC2
• Synonyms: EC 3.6.4.13; YTH domain-containing protein 2; hYTHDC2
• Gene Name: YTHDC2
• UniProt ID: YTDC2_HUMAN
• PDB ID: 2YU6; 6K6U; 6LR2
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF21010 ; PF04408 ; PF00271 ; PF07717 ; PF01424 ; PF04146
• Sequence:
  MSRPSSVSPRQPAPGGGGGGGPSPCGPGGGGRAKGLKDIRIDEEVKIAVNIALERFRYGD
  QREMEFPSSLTSTERAFIHRLSQSLGLVSKSKGKGANRYLTVKKKDGSETAHAMMTCNLT
  HNTKHAVRSLIQRFPVTNKERTELLPKTERGNVFAVEAENREMSKTSGRLNNGIPQIPVK
  RGESEFDSFRQSLPVFEKQEEIVKIIKENKVVLIVGETGSGKTTQIPQFLLDDCFKNGIP
  CRIFCTQPRRLAAIAVAERVAAERRERIGQTIGYQIRLESRVSPKTLLTFCTNGVLLRTL
  MAGDSTLSTVTHVIVDEVHERDRFSDFLLTKLRDLLQKHPTLKLILSSAALDVNLFIRYF
  GSCPVIYIQGRPFEVKEMFLEDILRTTGYTNKEMLKYKKEKQQEEKQQTTLTEWYSAQEN
  SFKPESQRQRTVLNVTDEYDLLDDGGDAVFSQLTEKDVNCLEPWLIKEMDACLSDIWLHK
  DIDAFAQVFHLILTENVSVDYRHSETSATALMVAAGRGFASQVEQLISMGANVHSKASNG
  WMALDWAKHFGQTEIVDLLESYSATLEFGNLDESSLVQTNGSDLSAEDRELLKAYHHSFD
  DEKVDLDLIMHLLYNICHSCDAGAVLIFLPGYDEIVGLRDRILFDDKRFADSTHRYQVFM
  LHSNMQTSDQKKVLKNPPAGVRKIILSTNIAETSITVNDVVFVIDSGKVKEKSFDALNFV
  TMLKMVWISKASAIQRKGRAGRCRPGICFRLFSRLRFQNMLEFQTPELLRMPLQELCLHT
  KLLAPVNCPIADFLMKAPEPPPALIVRNAVQMLKTIDAMDTWEDLTELGYHLADLPVEPH
  LGKMVLCAVVLKCLDPILTIACTLAYRDPFVLPTQASQKRAAMLCRKRFTAGAFSDHMAL
  LRAFQAWQKARSDGWERAFCEKNFLSQATMEIIIGMRTQLLGQLRASGFVRARGGGDIRD
  VNTNSENWAVVKAALVAGMYPNLVHVDRENLVLTGPKEKKVRFHPASVLSQPQYKKIPPA
  NGQAAAIKALPTDWLIYDEMTRAHRIANIRCCSAVTPVTILVFCGPARLASNALQEPSSF
  RVDGIPNDSSDSEMEDKTTANLAALKLDEWLHFTLEPEAASLLLQLRQKWHSLFLRRMRA
  PSKPWSQVDEATIRAIIAVLSTEEQSAGLQQPSGIGQRPRPMSSEELPLASSWRSNNSRK
  SSADTEFSDECTTAERVLMKSPSPALHPPQKYKDRGILHPKRGTEDRSDQSSLKSTDSSS
  YPSPCASPSPPSSGKGSKSPSPRPNMPVRYFIMKSSNLRNLEISQQKGIWSTTPSNERKL
  NRAFWESSIVYLVFSVQGSGHFQGFSRMSSEIGREKSQDWGSAGLGGVFKVEWIRKESLP
  FQFAHHLLNPWNDNKKVQISRDGQELEPLVGEQLLQLWERLPLGEKNTTD
• Function: 3'-5' RNA helicase that plays a key role in the male and female germline by promoting transition from mitotic to meiotic divisions in stem cells. Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, a modification present at internal sites of mRNAs and some non-coding RNAs that plays a role in the efficiency of RNA processing and stability. Essential for ensuring a successful progression of the meiotic program in the germline by regulating the level of m6A-containing RNAs. Acts by binding and promoting degradation of m6A-containing mRNAs: the 3'-5' RNA helicase activity is required for this process and RNA degradation may be mediated by XRN1 exoribonuclease. Required for both spermatogenesis and oogenesis.
• Tissue Specificity: Expressed in testis . Not detected in spermatogonia next to the tubule wall but is strongly expressed in spermatocytes, suggesting that it is up-regulated in germ cells upon entry into meiosis .

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 3'-5' RNA helicase YTHDC2.	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3'-5' RNA helicase YTHDC2.	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 3'-5' RNA helicase YTHDC2.	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 3'-5' RNA helicase YTHDC2.	[1]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 3'-5' RNA helicase YTHDC2.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3'-5' RNA helicase YTHDC2.	[5]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of 3'-5' RNA helicase YTHDC2.	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of 3'-5' RNA helicase YTHDC2.	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of 3'-5' RNA helicase YTHDC2.	[8]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of 3'-5' RNA helicase YTHDC2.	[1]
Clodronate	DM9Y6X7	Approved	Clodronate affects the expression of 3'-5' RNA helicase YTHDC2.	[1]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 3'-5' RNA helicase YTHDC2.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 3'-5' RNA helicase YTHDC2.	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of 3'-5' RNA helicase YTHDC2.	[10]

References

• [1] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [2] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] 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.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.