Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD4OLZK)

• DOT Name: DNA (DNMT3L)
• Synonyms: cytosine-5)-methyltransferase 3-like
• Gene Name: DNMT3L
• UniProt ID: DNM3L_HUMAN
• PDB ID: 2PV0; 2PVC; 2QRV; 4U7P; 4U7T; 5YX2; 6BRR; 6F57; 6KDA; 6KDB; 6KDL; 6KDP; 6KDT; 6U8P; 6U8V; 6U8W; 6U8X; 6U90; 6U91; 6W89; 6W8B; 6W8D; 6W8J; 7X9D
• Pfam ID: PF17980 ; PF21255
• Sequence:
  MAAIPALDPEAEPSMDVILVGSSELSSSVSPGTGRDLIAYEVKANQRNIEDICICCGSLQ
  VHTQHPLFEGGICAPCKDKFLDALFLYDDDGYQSYCSICCSGETLLICGNPDCTRCYCFE
  CVDSLVGPGTSGKVHAMSNWVCYLCLPSSRSGLLQRRRKWRSQLKAFYDRESENPLEMFE
  TVPVWRRQPVRVLSLFEDIKKELTSLGFLESGSDPGQLKHVVDVTDTVRKDVEEWGPFDL
  VYGATPPLGHTCDRPPSWYLFQFHRLLQYARPKPGSPRPFFWMFVDNLVLNKEDLDVASR
  FLEMEPVTIPDVHGGSLQNAVRVWSNIPAIRSRHWALVSEEELSLLAQNKQSSKLAAKWP
  TKLVKNCFLPLREYFKYFSTELTSSL
• Function: Catalytically inactive regulatory factor of DNA methyltransferases that can either promote or inhibit DNA methylation depending on the context. Essential for the function of DNMT3A and DNMT3B: activates DNMT3A and DNMT3B by binding to their catalytic domain. Acts by accelerating the binding of DNA and S-adenosyl-L-methionine (AdoMet) to the methyltransferases and dissociates from the complex after DNA binding to the methyltransferases. Recognizes unmethylated histone H3 lysine 4 (H3K4me0) and induces de novo DNA methylation by recruitment or activation of DNMT3. Plays a key role in embryonic stem cells and germ cells. In germ cells, required for the methylation of imprinted loci together with DNMT3A. In male germ cells, specifically required to methylate retrotransposons, preventing their mobilization. Plays a key role in embryonic stem cells (ESCs) by acting both as an positive and negative regulator of DNA methylation. While it promotes DNA methylation of housekeeping genes together with DNMT3A and DNMT3B, it also acts as an inhibitor of DNA methylation at the promoter of bivalent genes. Interacts with the EZH2 component of the PRC2/EED-EZH2 complex, preventing interaction of DNMT3A and DNMT3B with the PRC2/EED-EZH2 complex, leading to maintain low methylation levels at the promoters of bivalent genes. Promotes differentiation of ESCs into primordial germ cells by inhibiting DNA methylation at the promoter of RHOX5, thereby activating its expression.
• Tissue Specificity: Expressed at low levels in several tissues including testis, ovary, and thymus.
• Reactome Pathway: DNA methylation (R-HSA-5334118)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of DNA (DNMT3L).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA (DNMT3L).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of DNA (DNMT3L).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA (DNMT3L).	[4]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA (DNMT3L).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA (DNMT3L).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA (DNMT3L).	[7]

References

• [1] 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.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [5] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.