Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1L8Q48)

• DOT Name: tRNA methyltransferase 10 homolog C (TRMT10C)
• Synonyms: HBV pre-S2 trans-regulated protein 2; Mitochondrial ribonuclease P protein 1; Mitochondrial RNase P protein 1; RNA (guanine-9-)-methyltransferase domain-containing protein 1; Renal carcinoma antigen NY-REN-49; mRNA methyladenosine-N(1)-methyltransferase; EC 2.1.1.-; tRNA (adenine(9)-N(1))-methyltransferase; EC 2.1.1.218; tRNA (guanine(9)-N(1))-methyltransferase; EC 2.1.1.221
• Gene Name: TRMT10C
• Related Disease:
  Colorectal carcinoma
  Lactic acidosis
  Mitochondrial disease
  Combined oxidative phosphorylation defect type 30
• UniProt ID: TM10C_HUMAN
• PDB ID: 5NFJ; 7ONU
• EC Number: 2.1.1.-; 2.1.1.218; 2.1.1.221
• Pfam ID: PF01746
• Sequence:
  MAAFLKMSVSVNFFRPFTRFLVPFTLHRKRNNLTILQRYMSSKIPAVTYPKNESTPPSEE
  LELDKWKTTMKSSVQEECVSTISSSKDEDPLAATREFIEMWRLLGREVPEHITEEELKTL
  MECVSNTAKKKYLKYLYTKEKVKKARQIKKEMKAAAREEAKNIKLLETTEEDKQKNFLFL
  RLWDRNMDIAMGWKGAQAMQFGQPLVFDMAYENYMKRKELQNTVSQLLESEGWNRRNVDP
  FHIYFCNLKIDGALHRELVKRYQEKWDKLLLTSTEKSHVDLFPKDSIIYLTADSPNVMTT
  FRHDKVYVIGSFVDKSMQPGTSLAKAKRLNLATECLPLDKYLQWEIGNKNLTLDQMIRIL
  LCLKNNGNWQEALQFVPKRKHTGFLEISQHSQEFINRLKKAKT
• Function: Mitochondrial tRNA N(1)-methyltransferase involved in mitochondrial tRNA maturation. Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5'-ends. Together with HSD17B10/MRPP2, forms a subcomplex of the mitochondrial ribonuclease P, named MRPP1-MRPP2 subcomplex, which displays functions that are independent of the ribonuclease P activity. The MRPP1-MRPP2 subcomplex catalyzes the formation of N(1)-methylguanine and N(1)-methyladenine at position 9 (m1G9 and m1A9, respectively) in tRNAs; TRMT10C/MRPP1 acting as the catalytic N(1)-methyltransferase subunit. The MRPP1-MRPP2 subcomplex also acts as a tRNA maturation platform: following 5'-end cleavage by the mitochondrial ribonuclease P complex, the MRPP1-MRPP2 subcomplex enhances the efficiency of 3'-processing catalyzed by ELAC2, retains the tRNA product after ELAC2 processing and presents the nascent tRNA to the mitochondrial CCA tRNA nucleotidyltransferase TRNT1 enzyme. In addition to tRNA N(1)-methyltransferase activity, TRMT10C/MRPP1 also acts as a mRNA N(1)-methyltransferase by mediating methylation of adenosine residues at the N(1) position of MT-ND5 mRNA. Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.
• Reactome Pathway:
  tRNA modification in the mitochondrion (R-HSA-6787450)
  rRNA processing in the mitochondrion (R-HSA-8868766)
  tRNA processing in the mitochondrion (R-HSA-6785470)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Lactic acidosis	DISZI1ZK	moderate	Genetic Variation	[2]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[3]
Combined oxidative phosphorylation defect type 30	DISX1BBD	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[10]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[12]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[14]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of tRNA methyltransferase 10 homolog C (TRMT10C).	[15]

1 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 tRNA methyltransferase 10 homolog C (TRMT10C).	[13]

References

• [1] 17-Hydroxysteroid dehydrogenase type 10 predicts survival of patients with colorectal cancer and affects mitochondrial DNA content.Cancer Lett. 2016 Apr 28;374(1):149-155. doi: 10.1016/j.canlet.2016.02.011. Epub 2016 Feb 13.
• [2] Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies. Am J Hum Genet. 2016 May 5;98(5):993-1000. doi: 10.1016/j.ajhg.2016.03.010. Epub 2016 Apr 28.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [15] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.