Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRTUUM4)

• DOT Name: Peptide chain release factor 1, mitochondrial (MTRF1)
• Synonyms: MRF-1; MtRF-1
• Gene Name: MTRF1
• Related Disease:
  Kidney failure
  Chronic renal failure
  End-stage renal disease
• UniProt ID: RF1M_HUMAN
• PDB ID: 8OIN; 8OIP; 8OIQ; 8OIR; 8OIS; 8OIT
• Pfam ID: PF03462 ; PF00472
• Sequence:
  MNRHLCVWLFRHPSLNGYLQCHIQLHSHQFRQIHLDTRLQVFRQNRNCILHLLSKNWSRR
  YCHQDTKMLWKHKALQKYMENLSKEYQTLEQCLQHIPVNEENRRSLNRRHAELAPLAAIY
  QEIQETEQAIEELESMCKSLNKQDEKQLQELALEERQTIDQKINMLYNELFQSLVPKEKY
  DKNDVILEVTAGRTTGGDICQQFTREIFDMYQNYSCYKHWQFELLNYTPADYGGLHHAAA
  RISGDGVYKHLKYEGGIHRVQRIPEVGLSSRMQRIHTGTMSVIVLPQPDEVDVKLDPKDL
  RIDTFRAKGAGGQHVNKTDSAVRLVHIPTGLVVECQQERSQIKNKEIAFRVLRARLYQQI
  IEKDKRQQQSARKLQVGTRAQSERIRTYNFTQDRVSDHRIAYEVRDIKEFLCGGKGLDQL
  IQRLLQSADEEAIAELLDEHLKSAK
• Function: Mitochondrial peptide chain release factor that directs the termination of translation in response to the peptide chain non-canonical stop codons AGG and AGA. Non-canonical termination codons AGG and AGA are found at the end of MT-CO1/COX1 and MT-ND6/ND6 open reading frames, respectively. Recognizes non-canonical stop codons via a network of interactions between the codon, MTRF1 and the ribosomal RNA (rRNA): in contrast to other translation release factors, which identify the codon in the A-site via direct interactions of amino acid side chains with the bases, MTRF1 repositions the first 2 bases of the stop codon to use an intricate network of interactions that includes residues of the release factor, the rRNA of the small ribosomal subunit, as well as neighboring bases of the mRNA.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[1]
Chronic renal failure	DISGG7K6	Limited	Genetic Variation	[2]
End-stage renal disease	DISXA7GG	Limited	Genetic Variation	[2]

7 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 Peptide chain release factor 1, mitochondrial (MTRF1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peptide chain release factor 1, mitochondrial (MTRF1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peptide chain release factor 1, mitochondrial (MTRF1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peptide chain release factor 1, mitochondrial (MTRF1).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Peptide chain release factor 1, mitochondrial (MTRF1).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peptide chain release factor 1, mitochondrial (MTRF1).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Peptide chain release factor 1, mitochondrial (MTRF1).	[10]

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 affects the methylation of Peptide chain release factor 1, mitochondrial (MTRF1).	[8]

References

• [1] Evaluation of markers on human chromosome 10, including the homologue of the rodent Rf-1 gene, for linkage to ESRD in black patients.Am J Kidney Dis. 1999 Feb;33(2):294-300. doi: 10.1016/s0272-6386(99)70303-3.
• [2] Linkage heterogeneity of end-stage renal disease on human chromosome 10.Kidney Int. 2002 Sep;62(3):770-4. doi: 10.1046/j.1523-1755.2002.00534.x.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [10] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.