Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKB0N8Q)

• DOT Name: Repressor of RNA polymerase III transcription MAF1 homolog (MAF1)
• Gene Name: MAF1
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Colorectal carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Metabolic disorder
  Neoplasm
  Obesity
• UniProt ID: MAF1_HUMAN
• PDB ID: 3NR5
• Pfam ID: PF09174
• Sequence:
  MKLLENSSFEAINSQLTVETGDAHIIGRIESYSCKMAGDDKHMFKQFCQEGQPHVLEALS
  PPQTSGLSPSRLSKSQGGEEEGPLSDKCSRKTLFYLIATLNESFRPDYDFSTARSHEFSR
  EPSLSWVVNAVNCSLFSAVREDFKDLKPQLWNAVDEEICLAECDIYSYNPDLDSDPFGED
  GSLWSFNYFFYNKRLKRIVFFSCRSISGSTYTPSEAGNELDMELGEEEVEEESRSGGSGA
  EETSTMEEDRVPVICI
• Function: Plays a role in the repression of RNA polymerase III-mediated transcription in response to changing nutritional, environmental and cellular stress conditions to balance the production of highly abundant tRNAs, 5S rRNA, and other small non-coding RNAs with cell growth and maintenance. Also plays a key role in cell fate determination by promoting mesorderm induction and adipocyte differentiation. Mechanistically, associates with the RNA polymerase III clamp and thereby impairs its recruitment to the complex made of the promoter DNA, TBP and the initiation factor TFIIIB. When nutrients are available and mTOR kinase is active, MAF1 is hyperphosphorylated and RNA polymerase III is engaged in transcription. Stress-induced MAF1 dephosphorylation results in nuclear localization, increased targeting of gene-bound RNA polymerase III and a decrease in the transcriptional readout. Additionally, may also regulate RNA polymerase I and RNA polymerase II-dependent transcription through its ability to regulate expression of the central initiation factor TBP.
• Reactome Pathway: Regulation of PTEN gene transcription (R-HSA-8943724)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[4]

4 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 Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[13]

7 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 Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[9]
MLN4924	DMP36KD	Phase 3	MLN4924 increases the expression of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[2]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[14]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the degradation of Repressor of RNA polymerase III transcription MAF1 homolog (MAF1).	[2]

References

• [1] Mammalian Maf1 is a negative regulator of transcription by all three nuclear RNA polymerases.Mol Cell. 2007 May 11;26(3):367-79. doi: 10.1016/j.molcel.2007.03.021.
• [2] The RNA polymerase III repressor MAF1 is regulated by ubiquitin-dependent proteasome degradation and modulates cancer drug resistance and apoptosis. J Biol Chem. 2019 Dec 13;294(50):19255-19268. doi: 10.1074/jbc.RA119.008849. Epub 2019 Oct 23.
• [3] Involvement of MAF1homolog, negative regulator of RNA polymeraseIII in colorectal cancer progression.Int J Oncol. 2019 Mar;54(3):1001-1009. doi: 10.3892/ijo.2019.4678. Epub 2019 Jan 7.
• [4] Emerging Roles for Maf1 beyond the Regulation of RNA Polymerase III Activity.J Mol Biol. 2015 Aug 14;427(16):2577-85. doi: 10.1016/j.jmb.2015.06.022. Epub 2015 Jul 11.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] The RNA polymerase III repressor MAF1 is regulated by ubiquitin-dependent proteasome degradation and modulates cancer drug resistance and apoptosis. J Biol Chem. 2019 Dec 13;294(50):19255-19268. doi: 10.1074/jbc.RA119.008849. Epub 2019 Oct 23.
• [11] 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.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] 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.
• [14] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.