Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5Q8ZUJ)

• DOT Name: DNA-directed RNA polymerase, mitochondrial (POLRMT)
• Synonyms: MtRPOL; EC 2.7.7.6
• Gene Name: POLRMT
• Related Disease:
  Progressive external ophthalmoplegia
  Combined oxidative phosphorylation deficiency 55
  Hepatitis C virus infection
  Advanced cancer
  Leukoplakia
  Oral cancer
  Oral mucosa leukoplakia
• UniProt ID: RPOM_HUMAN
• PDB ID: 3SPA; 4BOC; 5OLA; 6ERP; 6ERQ; 7A8P; 7PZP; 7PZR; 7ZC4
• EC Number: 2.7.7.6
• Pfam ID: PF00940 ; PF14700
• Sequence:
  MSALCWGRGAAGLKRALRPCGRPGLPGKEGTAGGVCGPRRSSSASPQEQDQDRRKDWGHV
  ELLEVLQARVRQLQAESVSEVVVNRVDVARLPECGSGDGSLQPPRKVQMGAKDATPVPCG
  RWAKILEKDKRTQQMRMQRLKAKLQMPFQSGEFKALTRRLQVEPRLLSKQMAGCLEDCTR
  QAPESPWEEQLARLLQEAPGKLSLDVEQAPSGQHSQAQLSGQQQRLLAFFKCCLLTDQLP
  LAHHLLVVHHGQRQKRKLLTLDMYNAVMLGWARQGAFKELVYVLFMVKDAGLTPDLLSYA
  AALQCMGRQDQDAGTIERCLEQMSQEGLKLQALFTAVLLSEEDRATVLKAVHKVKPTFSL
  PPQLPPPVNTSKLLRDVYAKDGRVSYPKLHLPLKTLQCLFEKQLHMELASRVCVVSVEKP
  TLPSKEVKHARKTLKTLRDQWEKALCRALRETKNRLEREVYEGRFSLYPFLCLLDEREVV
  RMLLQVLQALPAQGESFTTLARELSARTFSRHVVQRQRVSGQVQALQNHYRKYLCLLASD
  AEVPEPCLPRQYWEELGAPEALREQPWPLPVQMELGKLLAEMLVQATQMPCSLDKPHRSS
  RLVPVLYHVYSFRNVQQIGILKPHPAYVQLLEKAAEPTLTFEAVDVPMLCPPLPWTSPHS
  GAFLLSPTKLMRTVEGATQHQELLETCPPTALHGALDALTQLGNCAWRVNGRVLDLVLQL
  FQAKGCPQLGVPAPPSEAPQPPEAHLPHSAAPARKAELRRELAHCQKVAREMHSLRAEAL
  YRLSLAQHLRDRVFWLPHNMDFRGRTYPCPPHFNHLGSDVARALLEFAQGRPLGPHGLDW
  LKIHLVNLTGLKKREPLRKRLAFAEEVMDDILDSADQPLTGRKWWMGAEEPWQTLACCME
  VANAVRASDPAAYVSHLPVHQDGSCNGLQHYAALGRDSVGAASVNLEPSDVPQDVYSGVA
  AQVEVFRRQDAQRGMRVAQVLEGFITRKVVKQTVMTVVYGVTRYGGRLQIEKRLRELSDF
  PQEFVWEASHYLVRQVFKSLQEMFSGTRAIQHWLTESARLISHMGSVVEWVTPLGVPVIQ
  PYRLDSKVKQIGGGIQSITYTHNGDISRKPNTRKQKNGFPPNFIHSLDSSHMMLTALHCY
  RKGLTFVSVHDCYWTHAADVSVMNQVCREQFVRLHSEPILQDLSRFLVKRFCSEPQKILE
  ASQLKETLQAVPKPGAFDLEQVKRSTYFFS
• Function: DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT that is required for basal transcription of mitochondrial DNA. In this complex, TFAM recruits POLRMT to a specific promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand. Has DNA primase activity. Catalyzes the synthesis of short RNA primers that are necessary for the initiation of lagging-strand DNA synthesis from the origin of light-strand DNA replication (OriL).
• Reactome Pathway:
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Mitochondrial transcription initiation (R-HSA-163282)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Progressive external ophthalmoplegia	DISX4ATI	Definitive	Genetic Variation	[1]
Combined oxidative phosphorylation deficiency 55	DIS1VG3L	Strong	Autosomal recessive	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[4]
Leukoplakia	DIST3QD3	Limited	Genetic Variation	[4]
Oral cancer	DISLD42D	Limited	Genetic Variation	[4]
Oral mucosa leukoplakia	DISJTL5X	Limited	Genetic Variation	[4]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Zidovudine	DM4KI7O	Approved	DNA-directed RNA polymerase, mitochondrial (POLRMT) increases the Cytogenetic abnormality ADR of Zidovudine.	[11]
Zalcitabine	DMH7MUV	Approved	DNA-directed RNA polymerase, mitochondrial (POLRMT) increases the Cytogenetic abnormality ADR of Zalcitabine.	[11]
Didanosine	DMI2QPE	Approved	DNA-directed RNA polymerase, mitochondrial (POLRMT) increases the Metabolic disorder ADR of Didanosine.	[11]

2 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-directed RNA polymerase, mitochondrial (POLRMT).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA-directed RNA polymerase, mitochondrial (POLRMT).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA-directed RNA polymerase, mitochondrial (POLRMT).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA-directed RNA polymerase, mitochondrial (POLRMT).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of DNA-directed RNA polymerase, mitochondrial (POLRMT).	[7]
INX-189	DMSTJ6Q	Phase 2	INX-189 decreases the expression of DNA-directed RNA polymerase, mitochondrial (POLRMT).	[8]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of DNA-directed RNA polymerase, mitochondrial (POLRMT).	[10]

References

• [1] Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia.Nat Struct Mol Biol. 2004 Aug;11(8):770-6. doi: 10.1038/nsmb805. Epub 2004 Jul 18.
• [2] Effect of inbreeding on intellectual disability revisited by trio sequencing. Clin Genet. 2019 Jan;95(1):151-159. doi: 10.1111/cge.13463. Epub 2018 Nov 19.
• [3] Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance.Front Mol Biosci. 2017 Nov 22;4:74. doi: 10.3389/fmolb.2017.00074. eCollection 2017.
• [4] Association of DNA sequence variation in mitochondrial DNA polymerase with mitochondrial DNA synthesis and risk of oral cancer.Gene. 2016 Jan 10;575(2 Pt 3):650-4. doi: 10.1016/j.gene.2015.09.039. Epub 2015 Sep 25.
• [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] 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.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Effects of BMS-986094, a Guanosine Nucleotide Analogue, on Mitochondrial DNA Synthesis and Function. Toxicol Sci. 2016 Oct;153(2):396-408. doi: 10.1093/toxsci/kfw135. Epub 2016 Jul 27.
• [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] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [11] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.