Details of Drug Off-Target (DOT)

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

• DOT Name: DNA polymerase subunit gamma-2 (POLG2)
• Synonyms: DNA polymerase gamma accessory 55 kDa subunit; p55; Mitochondrial DNA polymerase accessory subunit; MtPolB; PolG-beta
• Gene Name: POLG2
• Related Disease:
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
  Acute lymphocytic leukaemia
  Adult glioblastoma
  Adult respiratory distress syndrome
  Ankylosing spondylitis
  Bone osteosarcoma
  Cerebellar disorder
  Classic Hodgkin lymphoma
  Cryohydrocytosis
  Glioblastoma multiforme
  Mitochondrial disease
  Mixed connective tissue disease
  Monocytic leukemia
  Multiple sclerosis
  Myopathy
  Nervous system disease
  Osteoarthritis
  Osteosarcoma
  Parkinsonian disorder
  Progressive external ophthalmoplegia
  Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4
  Ptosis
  Rheumatoid arthritis
  Sarcoidosis
  Subacute cutaneous lupus erythematosus
  Systemic lupus erythematosus
  T-cell leukaemia
  Acute liver failure
  Bladder cancer
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Mitochondrial DNA depletion syndrome
  Type-1 diabetes
  Urinary bladder cancer
  Autosomal dominant progressive external ophthalmoplegia
  Pneumonia
  Acute myelogenous leukaemia
  Advanced cancer
  Arthritis
  Leukoplakia
  Liver failure
  Mitochondrial DNA depletion syndrome 16 (hepatic type)
  Neoplasm
  Oral cancer
  Pneumocystis pneumonia
• UniProt ID: DPOG2_HUMAN
• PDB ID: 2G4C; 3IKL; 3IKM; 4ZTU; 4ZTZ; 5C51; 5C52; 5C53; 8D33; 8D37; 8D3R; 8D42
• Pfam ID: PF03129
• Sequence:
  MRSRVAVRACHKVCRCLLSGFGGRVDAGQPELLTERSSPKGGHVKSHAELEGNGEHPEAP
  GSGEGSEALLEICQRRHFLSGSKQQLSRDSLLSGCHPGFGPLGVELRKNLAAEWWTSVVV
  FREQVFPVDALHHKPGPLLPGDSAFRLVSAETLREILQDKELSKEQLVAFLENVLKTSGK
  LRENLLHGALEHYVNCLDLVNKRLPYGLAQIGVCFHPVFDTKQIRNGVKSIGEKTEASLV
  WFTPPRTSNQWLDFWLRHRLQWWRKFAMSPSNFSSSDCQDEEGRKGNKLYYNFPWGKELI
  ETLWNLGDHELLHMYPGNVSKLHGRDGRKNVVPCVLSVNGDLDRGMLAYLYDSFQLTENS
  FTRKKNLHRKVLKLHPCLAPIKVALDVGRGPTLELRQVCQGLFNELLENGISVWPGYLET
  MQSSLEQLYSKYDEMSILFTVLVTETTLENGLIHLRSRDTTMKEMMHISKLKDFLIKYIS
  SAKNV
• Function: Accessory subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA). Acts as an allosteric regulator of the holoenzyme activities. Enhances the polymerase activity and the processivity of POLG by increasing its interactions with the DNA template. Suppresses POLG exonucleolytic proofreading especially toward homopolymeric templates bearing mismatched termini. Binds to single-stranded DNA.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway: Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Definitive	Biomarker	[1]
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	DIS9NLHF	Definitive	GermlineCausalMutation	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[5]
Ankylosing spondylitis	DISRC6IR	Strong	Genetic Variation	[6]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[7]
Cerebellar disorder	DIS2O7WM	Strong	Biomarker	[8]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[9]
Cryohydrocytosis	DISMQHL3	Strong	Genetic Variation	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[11]
Mixed connective tissue disease	DISXX0H8	Strong	Biomarker	[12]
Monocytic leukemia	DIS8M755	Strong	Biomarker	[13]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[6]
Myopathy	DISOWG27	Strong	Genetic Variation	[14]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[15]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[16]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[7]
Parkinsonian disorder	DISHGY45	Strong	Biomarker	[8]
Progressive external ophthalmoplegia	DISX4ATI	Strong	Genetic Variation	[17]
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	DISSXAMN	Strong	Autosomal dominant	[18]
Ptosis	DISJZNIY	Strong	Genetic Variation	[14]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[19]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[20]
Subacute cutaneous lupus erythematosus	DIS6XDK0	Strong	Biomarker	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[12]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[21]
Acute liver failure	DIS5EZKX	moderate	Genetic Variation	[17]
Bladder cancer	DISUHNM0	moderate	Genetic Variation	[22]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Altered Expression	[23]
Liver cancer	DISDE4BI	moderate	Altered Expression	[23]
Mitochondrial DNA depletion syndrome	DISIGZSM	Moderate	Semidominant	[17]
Type-1 diabetes	DIS7HLUB	moderate	Altered Expression	[24]
Urinary bladder cancer	DISDV4T7	moderate	Genetic Variation	[22]
Autosomal dominant progressive external ophthalmoplegia	DISXBSXA	Supportive	Autosomal dominant	[2]
Pneumonia	DIS8EF3M	Disputed	Biomarker	[25]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[26]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[27]
Arthritis	DIST1YEL	Limited	Genetic Variation	[28]
Leukoplakia	DIST3QD3	Limited	Biomarker	[27]
Liver failure	DISLGEL6	Limited	Genetic Variation	[29]
Mitochondrial DNA depletion syndrome 16 (hepatic type)	DISA3OOG	Limited	Autosomal recessive	[30]
Neoplasm	DISZKGEW	Limited	Biomarker	[31]
Oral cancer	DISLD42D	Limited	Genetic Variation	[27]
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[32]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	DNA polymerase subunit gamma-2 (POLG2) affects the response to substance of DTI-015.	[43]

8 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 DNA polymerase subunit gamma-2 (POLG2).	[33]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA polymerase subunit gamma-2 (POLG2).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA polymerase subunit gamma-2 (POLG2).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA polymerase subunit gamma-2 (POLG2).	[36]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA polymerase subunit gamma-2 (POLG2).	[37]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA polymerase subunit gamma-2 (POLG2).	[38]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of DNA polymerase subunit gamma-2 (POLG2).	[39]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of DNA polymerase subunit gamma-2 (POLG2).	[42]

2 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 DNA polymerase subunit gamma-2 (POLG2).	[40]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DNA polymerase subunit gamma-2 (POLG2).	[41]

References

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• [22] A polymorphism of the POLG2 gene is genetically associated with the invasiveness of urinary bladder cancer in Japanese males.J Hum Genet. 2011 Aug;56(8):572-6. doi: 10.1038/jhg.2011.60. Epub 2011 Jul 7.
• [23] Phenotypic and functional differences between human liver cancer endothelial cells and liver sinusoidal endothelial cells.J Vasc Res. 2008;45(1):78-86. doi: 10.1159/000109079. Epub 2007 Sep 27.
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• [27] 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.
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• [35] 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.
• [36] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [37] Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol In Vitro. 2021 Jun;73:105107. doi: 10.1016/j.tiv.2021.105107. Epub 2021 Feb 3.
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• [39] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
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• [41] 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.
• [42] 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.
• [43] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.