Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDUCT04)

• DOT Name: DNA polymerase subunit gamma-1 (POLG)
• Synonyms: EC 2.7.7.7; 3'-5' exodeoxyribonuclease; EC 3.1.11.-; 5'-deoxyribose-phosphate lyase; EC 4.2.99.-; Mitochondrial DNA polymerase catalytic subunit; PolG-alpha
• Gene Name: POLG
• Related Disease:
  Epilepsy
  Migraine disorder
  Mitochondrial DNA depletion syndrome 4a
  Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
  Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
  3-methylglutaconic aciduria
  Acute liver failure
  Attention deficit hyperactivity disorder
  Autism
  Autosomal recessive juvenile Parkinson disease 2
  Bipolar disorder
  Cataract
  Demyelinating polyneuropathy
  Depression
  Dilated cardiomyopathy
  Fatty liver disease
  Gastroparesis
  Hepatocellular carcinoma
  Hypothyroidism
  Juvenile-onset Parkinson disease
  Lactic acidosis
  Liver cancer
  Liver failure
  Mitochondrial DNA depletion syndrome
  Mitochondrial myopathy
  Mood disorder
  Obesity
  Pathologic nystagmus
  Polyneuropathy
  Sensorineural hearing loss disorder
  Sensory ataxia
  Status epilepticus seizure
  Cardiomyopathy
  Isolated congenital microcephaly
  Autosomal dominant progressive external ophthalmoplegia
  Autosomal recessive progressive external ophthalmoplegia
  Mitochondrial neurogastrointestinal encephalomyopathy
  Recessive mitochondrial ataxia syndrome
  Spinocerebellar ataxia with epilepsy
  Leigh syndrome
  Myopathy
• UniProt ID: DPOG1_HUMAN
• PDB ID: 3IKM; 4ZTU; 4ZTZ; 5C51; 5C52; 5C53; 8D33; 8D37; 8D3R; 8D42
• EC Number: 2.7.7.7; 3.1.11.-; 4.2.99.-
• Pfam ID: PF18136
• Sequence:
  MSRLLWRKVAGATVGPGPVPAPGRWVSSSVPASDPSDGQRRRQQQQQQQQQQQQQPQQPQ
  VLSSEGGQLRHNPLDIQMLSRGLHEQIFGQGGEMPGEAAVRRSVEHLQKHGLWGQPAVPL
  PDVELRLPPLYGDNLDQHFRLLAQKQSLPYLEAANLLLQAQLPPKPPAWAWAEGWTRYGP
  EGEAVPVAIPEERALVFDVEVCLAEGTCPTLAVAISPSAWYSWCSQRLVEERYSWTSQLS
  PADLIPLEVPTGASSPTQRDWQEQLVVGHNVSFDRAHIREQYLIQGSRMRFLDTMSMHMA
  ISGLSSFQRSLWIAAKQGKHKVQPPTKQGQKSQRKARRGPAISSWDWLDISSVNSLAEVH
  RLYVGGPPLEKEPRELFVKGTMKDIRENFQDLMQYCAQDVWATHEVFQQQLPLFLERCPH
  PVTLAGMLEMGVSYLPVNQNWERYLAEAQGTYEELQREMKKSLMDLANDACQLLSGERYK
  EDPWLWDLEWDLQEFKQKKAKKVKKEPATASKLPIEGAGAPGDPMDQEDLGPCSEEEEFQ
  QDVMARACLQKLKGTTELLPKRPQHLPGHPGWYRKLCPRLDDPAWTPGPSLLSLQMRVTP
  KLMALTWDGFPLHYSERHGWGYLVPGRRDNLAKLPTGTTLESAGVVCPYRAIESLYRKHC
  LEQGKQQLMPQEAGLAEEFLLTDNSAIWQTVEELDYLEVEAEAKMENLRAAVPGQPLALT
  ARGGPKDTQPSYHHGNGPYNDVDIPGCWFFKLPHKDGNSCNVGSPFAKDFLPKMEDGTLQ
  AGPGGASGPRALEINKMISFWRNAHKRISSQMVVWLPRSALPRAVIRHPDYDEEGLYGAI
  LPQVVTAGTITRRAVEPTWLTASNARPDRVGSELKAMVQAPPGYTLVGADVDSQELWIAA
  VLGDAHFAGMHGCTAFGWMTLQGRKSRGTDLHSKTATTVGISREHAKIFNYGRIYGAGQP
  FAERLLMQFNHRLTQQEAAEKAQQMYAATKGLRWYRLSDEGEWLVRELNLPVDRTEGGWI
  SLQDLRKVQRETARKSQWKKWEVVAERAWKGGTESEMFNKLESIATSDIPRTPVLGCCIS
  RALEPSAVQEEFMTSRVNWVVQSSAVDYLHLMLVAMKWLFEEFAIDGRFCISIHDEVRYL
  VREEDRYRAALALQITNLLTRCMFAYKLGLNDLPQSVAFFSAVDIDRCLRKEVTMDCKTP
  SNPTGMERRYGIPQGEALDIYQIIELTKGSLEKRSQPGP
• Function: Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA). Replicates both heavy and light strands of the circular mtDNA genome using a single-stranded DNA template, RNA primers and the four deoxyribonucleoside triphosphates as substrates. Has 5' -> 3' polymerase activity. Functionally interacts with TWNK and SSBP1 at the replication fork to form a highly processive replisome, where TWNK unwinds the double-stranded DNA template prior to replication and SSBP1 covers the parental heavy strand to enable continuous replication of the entire mitochondrial genome. A single nucleotide incorporation cycle includes binding of the incoming nucleotide at the insertion site, a phosphodiester bond formation reaction that extends the 3'-end of the primer DNA, and translocation of the primer terminus to the post-insertion site. After completing replication of a mtDNA strand, mediates 3' -> 5' exonucleolytic degradation at the nick to enable proper ligation. Highly accurate due to high nucleotide selectivity and 3' -> 5' exonucleolytic proofreading. Proficiently corrects base substitutions, single-base additions and deletions in non-repetitive sequences and short repeats, but displays lower proofreading activity when replicating longer homopolymeric stretches. Exerts exonuclease activity toward single-stranded DNA and double-stranded DNA containing 3'-terminal mispairs. When a misincorporation occurs, transitions from replication to a pro-nucleolytic editing mode and removes the missincorporated nucleoside in the exonuclease active site. Proceeds via an SN2 nucleolytic mechanism in which Asp-198 catalyzes phosphodiester bond hydrolysis and Glu-200 stabilizes the leaving group. As a result the primer strand becomes one nucleotide shorter and is positioned in the post-insertion site, ready to resume DNA synthesis. Exerts 5'-deoxyribose phosphate (dRP) lyase activity and mediates repair-associated mtDNA synthesis (gap filling) in base-excision repair pathway. Catalyzes the release of the 5'-terminal 2-deoxyribose-5-phosphate sugar moiety from incised apurinic/apyrimidinic (AP) sites to produce a substrate for DNA ligase. The dRP lyase reaction does not require divalent metal ions and likely proceeds via a Schiff base intermediate in a beta-elimination reaction mechanism.
• KEGG Pathway: Base excision repair (hsa03410)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Migraine disorder	DISFCQTG	Definitive	Genetic Variation	[2]
Mitochondrial DNA depletion syndrome 4a	DISU4RVU	Definitive	Autosomal recessive	[3]
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	DIS9NLHF	Definitive	Autosomal dominant	[3]
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	DISC52SS	Definitive	Autosomal recessive	[4]
3-methylglutaconic aciduria	DIS8G1WP	Strong	Genetic Variation	[5]
Acute liver failure	DIS5EZKX	Strong	CausalMutation	[6]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[7]
Autism	DISV4V1Z	Strong	Genetic Variation	[7]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Strong	Biomarker	[8]
Bipolar disorder	DISAM7J2	Strong	CausalMutation	[6]
Cataract	DISUD7SL	Strong	Genetic Variation	[9]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Genetic Variation	[10]
Depression	DIS3XJ69	Strong	Biomarker	[11]
Dilated cardiomyopathy	DISX608J	Strong	Altered Expression	[12]
Fatty liver disease	DIS485QZ	Strong	CausalMutation	[13]
Gastroparesis	DISDW0SR	Strong	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	Strong	SusceptibilityMutation	[15]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[7]
Juvenile-onset Parkinson disease	DISNT5BI	Strong	Biomarker	[8]
Lactic acidosis	DISZI1ZK	Strong	Genetic Variation	[16]
Liver cancer	DISDE4BI	Strong	SusceptibilityMutation	[15]
Liver failure	DISLGEL6	Strong	Genetic Variation	[17]
Mitochondrial DNA depletion syndrome	DISIGZSM	Strong	Genetic Variation	[18]
Mitochondrial myopathy	DIS9SA7V	Strong	Genetic Variation	[5]
Mood disorder	DISLVMWO	Strong	Biomarker	[19]
Obesity	DIS47Y1K	Strong	CausalMutation	[20]
Pathologic nystagmus	DIS1QSPO	Strong	Genetic Variation	[21]
Polyneuropathy	DISB9G3W	Strong	CausalMutation	[6]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[22]
Sensory ataxia	DISSMCYQ	Strong	CausalMutation	[6]
Status epilepticus seizure	DISY3BIC	Strong	Genetic Variation	[2]
Cardiomyopathy	DISUPZRG	moderate	Genetic Variation	[23]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[24]
Autosomal dominant progressive external ophthalmoplegia	DISXBSXA	Supportive	Autosomal dominant	[25]
Autosomal recessive progressive external ophthalmoplegia	DISY53WH	Supportive	Autosomal recessive	[25]
Mitochondrial neurogastrointestinal encephalomyopathy	DIS5HV4H	Supportive	Autosomal recessive	[26]
Recessive mitochondrial ataxia syndrome	DISQE1LU	Supportive	Autosomal recessive	[27]
Spinocerebellar ataxia with epilepsy	DISYMLLZ	Supportive	Autosomal recessive	[27]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[28]
Myopathy	DISOWG27	Limited	Genetic Variation	[29]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	DNA polymerase subunit gamma-1 (POLG) increases the response to substance of Valproate.	[41]
Fluorouracil	DMUM7HZ	Approved	DNA polymerase subunit gamma-1 (POLG) affects the response to substance of Fluorouracil.	[42]

11 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 polymerase subunit gamma-1 (POLG).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA polymerase subunit gamma-1 (POLG).	[31]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA polymerase subunit gamma-1 (POLG).	[33]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DNA polymerase subunit gamma-1 (POLG).	[33]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of DNA polymerase subunit gamma-1 (POLG).	[34]
Chloramphenicol	DMFXEWT	Approved	Chloramphenicol increases the expression of DNA polymerase subunit gamma-1 (POLG).	[35]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DNA polymerase subunit gamma-1 (POLG).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of DNA polymerase subunit gamma-1 (POLG).	[37]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of DNA polymerase subunit gamma-1 (POLG).	[38]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA polymerase subunit gamma-1 (POLG).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA polymerase subunit gamma-1 (POLG).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of DNA polymerase subunit gamma-1 (POLG).	[32]

References

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• [2] The spectrum of epilepsy caused by POLG mutations.Acta Neurol Belg. 2016 Mar;116(1):17-25. doi: 10.1007/s13760-015-0499-8. Epub 2015 Jun 24.
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] POLG mutation in a patient with cataracts, early-onset distal muscle weakness and atrophy, ovarian dysgenesis and 3-methylglutaconic aciduria.Gene. 2012 May 10;499(1):209-12. doi: 10.1016/j.gene.2012.02.034. Epub 2012 Mar 3.
• [6] The adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent-onset POLG-related mitochondrial disease.Epilepsia Open. 2018 Jan 11;3(1):103-108. doi: 10.1002/epi4.12094. eCollection 2018 Mar.
• [7] Understanding the Epilepsy in POLG Related Disease.Int J Mol Sci. 2017 Aug 24;18(9):1845. doi: 10.3390/ijms18091845.
• [8] Alpers syndrome with prominent white matter changes.Brain Dev. 2008 Apr;30(4):295-300. doi: 10.1016/j.braindev.2007.08.009. Epub 2007 Oct 17.
• [9] Neuromyopathy with congenital cataracts and glaucoma: a distinct syndrome caused by POLG variants.Eur J Hum Genet. 2018 Mar;26(3):367-373. doi: 10.1038/s41431-017-0003-4. Epub 2018 Jan 22.
• [10] Leukoencephalopathy with a case of heterozygous POLG mutation mimicking mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).J Clin Neurosci. 2019 Mar;61:302-304. doi: 10.1016/j.jocn.2018.10.054. Epub 2018 Oct 29.
• [11] A novel electrospun hydroxypropyl methylcellulose/polyethylene oxide blend nanofibers: Morphology and physicochemical properties.Carbohydr Polym. 2018 Feb 1;181:234-246. doi: 10.1016/j.carbpol.2017.10.071. Epub 2017 Oct 23.
• [12] A crucial role of mitochondrial Hsp40 in preventing dilated cardiomyopathy.Nat Med. 2006 Jan;12(1):128-32. doi: 10.1038/nm1327. Epub 2005 Dec 4.
• [13] Predicting the contribution of novel POLG mutations to human disease through analysis in yeast model.Mitochondrion. 2011 Jan;11(1):182-90. doi: 10.1016/j.mito.2010.09.007. Epub 2010 Sep 29.
• [14] Novel mutation in spacer region of POLG associated with ataxia neuropathy spectrum and gastroparesis.Auton Neurosci. 2012 Sep 25;170(1-2):70-2. doi: 10.1016/j.autneu.2012.06.002. Epub 2012 Jul 16.
• [15] Polymorphisms in POLG were associated with the prognosis and mtDNA content in hepatocellular carcinoma patients.Bull Cancer. 2017 Jun;104(6):500-507. doi: 10.1016/j.bulcan.2017.02.005. Epub 2017 Apr 28.
• [16] Two novel POLG mutations causing hepatic mitochondrial DNA depletion with recurrent hypoketotic hypoglycaemia and fatal liver dysfunction.Dig Liver Dis. 2009 Jul;41(7):494-9. doi: 10.1016/j.dld.2008.11.013. Epub 2009 Feb 4.
• [17] A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma.Hum Mol Genet. 2017 Jul 1;26(13):2515-2525. doi: 10.1093/hmg/ddx146.
• [18] Common genetic etiology between "multiple sclerosis-like" single-gene disorders and familial multiple sclerosis.Hum Genet. 2017 Jun;136(6):705-714. doi: 10.1007/s00439-017-1784-9. Epub 2017 Mar 23.
• [19] Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.Psychiatry Clin Neurosci. 2017 Aug;71(8):518-529. doi: 10.1111/pcn.12496. Epub 2017 Feb 8.
• [20] Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.Hum Mutat. 2008 Sep;29(9):E150-72. doi: 10.1002/humu.20824.
• [21] Genetic aetiology of ophthalmological manifestations in children - a focus on mitochondrial disease-related symptoms.Acta Ophthalmol. 2016 Feb;94(1):83-91. doi: 10.1111/aos.12897. Epub 2015 Oct 8.
• [22] POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness.Neurology. 2004 Jan 27;62(2):316-8. doi: 10.1212/wnl.62.2.316.
• [23] Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma.Lab Invest. 2007 Apr;87(4):326-35. doi: 10.1038/labinvest.3700523. Epub 2006 Feb 19.
• [24] Phenotypic and genotypic variability in Alpers syndrome. Eur J Paediatr Neurol. 2012 Jul;16(4):379-89. doi: 10.1016/j.ejpn.2011.12.006. Epub 2012 Jan 10.
• [25] Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001 Jul;28(3):211-2. doi: 10.1038/90034.
• [26] Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet. 2003 Jul;11(7):547-9. doi: 10.1038/sj.ejhg.5201002.
• [27] Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Neurology. 2005 Apr 12;64(7):1204-8. doi: 10.1212/01.WNL.0000156516.77696.5A.
• [28] 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.
• [29] Distal myopathy with cachexia: an unrecognised phenotype caused by dominantly-inherited mitochondrial polymerase mutations.J Neurol Neurosurg Psychiatry. 2013 Jan;84(1):107-10. doi: 10.1136/jnnp-2012-303232. Epub 2012 Aug 29.
• [30] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [31] 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.
• [32] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [33] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [34] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [35] The effect of ethidium bromide and chloramphenicol on mitochondrial biogenesis in primary human fibroblasts. Toxicol Appl Pharmacol. 2012 May 15;261(1):42-9. doi: 10.1016/j.taap.2012.03.009.
• [36] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [37] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [38] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [39] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [40] Identification of a Mitochondrial DNA Polymerase Affecting Cardiotoxicity of Sunitinib Using a Genome-Wide Screening on S. pombe Deletion Library. Toxicol Sci. 2016 Jan;149(1):4-14. doi: 10.1093/toxsci/kfv210. Epub 2015 Sep 18.
• [41] Clonally expanded mitochondrial DNA mutations in epileptic individuals with mutated DNA polymerase gamma. J Neuropathol Exp Neurol. 2008 Sep;67(9):857-66. doi: 10.1097/NEN.0b013e3181839b2d.
• [42] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.