POLG explained

DNA polymerase subunit gamma (POLG or POLG1) is an enzyme that in humans is encoded by the POLG gene.^[1] Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE).

Structure

POLG is located on the q arm of chromosome 15 in position 26.1 and has 23 exons. The POLG gene produces a 140 kDa protein composed of 1239 amino acids.^{[2] [3]} POLG, the protein encoded by this gene, is a member of the DNA polymerase type-A family. It is a mitochondrion nucleiod with an Mg2+ cofactor and 15 turns, 52 beta strands, and 39 alpha helixes.^{[4] [5]} POLG contains a polyglutamine tract near its N-terminus that may be polymorphic. Two transcript variants encoding the same protein have been found for this gene.

Function

POLG is a gene that codes for the catalytic subunit of the mitochondrial DNA polymerase, called DNA polymerase gamma.^[6] The human POLG cDNA and gene were cloned and mapped to chromosome band 15q25.^[7] In eukaryotic cells, the mitochondrial DNA is replicated by DNA polymerase gamma, a trimeric protein complex composed of a catalytic subunit, POLG, and a dimeric accessory subunit of 55 kDa encoded by the POLG2 gene.^[8] The catalytic subunit contains three enzymatic activities, a DNA polymerase activity, a 3’-5’ exonuclease activity that proofreads misincorporated nucleotides, and a 5’-dRP lyase activity required for base excision repair.

Catalytic activity

Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1).

Clinical significance

Mutations in the POLG gene are associated with several mitochondrial diseases, progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Pathogenic variants have also been linked with fatal congenital myopathy and gastrointestinal pseudo-obstruction and fatal infantile hepatic failure.^{[9] [10]} A list of all published mutations in the POLG coding region and their associated disease can be found at the Human DNA Polymerase Gamma Mutation Database.

Mice heterozygous for a Polg mutation are only able to replicate their mitochondrial DNA inaccurately, so that they sustain a 500-fold higher mutation burden than normal mice. These mice show no clear features of rapidly accelerated aging, indicating that mitochondrial mutations do not have a causal role in natural aging.^[11]

Interactions

POLG has been shown to have 50 binary protein-protein interactions including 32 co-complex interactions. POLG appears to interact with POLG2, Dlg4, Tp53, and Sod2.^[12]

Further reading

• Graziewicz MA, Longley MJ, Copeland WC . DNA polymerase gamma in mitochondrial DNA replication and repair . Chemical Reviews . 106 . 2 . 383–405 . February 2006 . 16464011 . 10.1021/cr040463d .
• Hudson G, Chinnery PF . Mitochondrial DNA polymerase-gamma and human disease . Human Molecular Genetics . 15 Spec No 2 . R244-52 . October 2006 . 16987890 . 10.1093/hmg/ddl233 . free .
• Lestienne P . Evidence for a direct role of the DNA polymerase gamma in the replication of the human mitochondrial DNA in vitro . Biochemical and Biophysical Research Communications . 146 . 3 . 1146–53 . August 1987 . 3619920 . 10.1016/0006-291X(87)90767-4 .
• Ropp PA, Copeland WC . Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma . Genomics . 36 . 3 . 449–58 . September 1996 . 8884268 . 10.1006/geno.1996.0490 .
• Lecrenier N, Van Der Bruggen P, Foury F . Mitochondrial DNA polymerases from yeast to man: a new family of polymerases . Gene . 185 . 1 . 147–52 . January 1997 . 9034326 . 10.1016/S0378-1119(96)00663-4 .
• Walker RL, Anziano P, Meltzer PS . A PAC containing the human mitochondrial DNA polymerase gamma gene (POLG) maps to chromosome 15q25 . Genomics . 40 . 2 . 376–8 . March 1997 . 9119411 . 10.1006/geno.1996.4580 .
• Kapsa RM, Quigley AF, Han TF, Jean-Francois MJ, Vaughan P, Byrne E . mtDNA replicative potential remains constant during ageing: polymerase gamma activity does not correlate with age related cytochrome oxidase activity decline in platelets . Nucleic Acids Research . 26 . 19 . 4365–73 . October 1998 . 9742236 . 147866 . 10.1093/nar/26.19.4365 .
• Spelbrink JN, Toivonen JM, Hakkaart GA, Kurkela JM, Cooper HM, Lehtinen SK, Lecrenier N, Back JW, Speijer D, Foury F, Jacobs HT . In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells . The Journal of Biological Chemistry . 275 . 32 . 24818–28 . August 2000 . 10827171 . 10.1074/jbc.M000559200 . free .
• Van Goethem G, Dermaut B, Löfgren A, Martin JJ, Van Broeckhoven C . Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions . Nature Genetics . 28 . 3 . 211–2 . July 2001 . 11431686 . 10.1038/90034 . 35417835 .
• Hirano M, DiMauro S . ANT1, Twinkle, POLG, and TP: new genes open our eyes to ophthalmoplegia . Neurology . 57 . 12 . 2163–5 . December 2001 . 11756592 . 10.1212/wnl.57.12.2163 . 42784334 .
• Ponamarev MV, Longley MJ, Nguyen D, Kunkel TA, Copeland WC . Active site mutation in DNA polymerase gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis . The Journal of Biological Chemistry . 277 . 18 . 15225–8 . May 2002 . 11897778 . 10.1074/jbc.C200100200 . free .
• Nitanai Y, Satow Y, Adachi H, Tsujimoto M . Crystal structure of human renal dipeptidase involved in beta-lactam hydrolysis . Journal of Molecular Biology . 321 . 2 . 177–84 . August 2002 . 12144777 . 10.1016/S0022-2836(02)00632-0 .
• Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei S, Papadimitriou A, Spelbrink H, Silvestri L, Casari G, Comi GP, Zeviani M . Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia . Annals of Neurology . 52 . 2 . 211–9 . August 2002 . 12210792 . 10.1002/ana.10278 . 8324826 .
• Van Goethem G, Martin JJ, Dermaut B, Löfgren A, Wibail A, Ververken D, Tack P, Dehaene I, Van Zandijcke M, Moonen M, Ceuterick C, De Jonghe P, Van Broeckhoven C . Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia . Neuromuscular Disorders . 13 . 2 . 133–42 . February 2003 . 12565911 . 10.1016/S0960-8966(02)00216-X . 2159997 .
• Jazayeri M, Andreyev A, Will Y, Ward M, Anderson CM, Clevenger W . Inducible expression of a dominant negative DNA polymerase-gamma depletes mitochondrial DNA and produces a rho0 phenotype . The Journal of Biological Chemistry . 278 . 11 . 9823–30 . March 2003 . 12645575 . 10.1074/jbc.M211730200 . free .
• Garrido N, Griparic L, Jokitalo E, Wartiovaara J, van der Bliek AM, Spelbrink JN . Composition and dynamics of human mitochondrial nucleoids . Molecular Biology of the Cell . 14 . 4 . 1583–96 . April 2003 . 12686611 . 153124 . 10.1091/mbc.E02-07-0399 .
• Agostino A, Valletta L, Chinnery PF, Ferrari G, Carrara F, Taylor RW, Schaefer AM, Turnbull DM, Tiranti V, Zeviani M . Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO) . Neurology . 60 . 8 . 1354–6 . April 2003 . 12707443 . 10.1212/01.wnl.0000056088.09408.3c . 31209510 .
• Van Goethem G, Schwartz M, Löfgren A, Dermaut B, Van Broeckhoven C, Vissing J . Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy . European Journal of Human Genetics . 11 . 7 . 547–9 . July 2003 . 12825077 . 10.1038/sj.ejhg.5201002 . free .
• Zullo SJ, Butler L, Zahorchak RJ, Macville M, Wilkes C, Merril CR . Localization by fluorescence in situ hybridization (FISH) of human mitochondrial polymerase gamma (POLG) to human chromosome band 15q24→q26, and of mouse mitochondrial polymerase gamma (Polg) to mouse chromosome band 7E, with confirmation by direct sequence analysis of bacterial artificial chromosomes (BACs) . Cytogenetics and Cell Genetics . 78 . 3–4 . 281–4 . Mar 1998 . 9465903 . 10.1159/000134672 .

External links

• GeneReviews/NCBI/NIH/UW entry on POLG-Related Disorders

Notes and References

1. Zullo SJ, Butler L, Zahorchak RJ, Macville M, Wilkes C, Merril CR . Localization by fluorescence in situ hybridization (FISH) of human mitochondrial polymerase gamma (POLG) to human chromosome band 15q24→q26, and of mouse mitochondrial polymerase gamma (Polg) to mouse chromosome band 7E, with confirmation by direct sequence analysis of bacterial artificial chromosomes (BACs) . Cytogenetics and Cell Genetics . 78 . 3–4 . 281–4 . Mar 1998 . 9465903 . 10.1159/000134672 .
2. Web site: Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information. Yao. Daniel. amino.heartproteome.org. 2018-08-28. 2018-08-29. https://web.archive.org/web/20180829072241/https://amino.heartproteome.org/web/protein/Q9U208. dead.
3. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
4. Web site: POLG - DNA polymerase subunit gamma-1 - Homo sapiens (Human) - POLG gene & protein. www.uniprot.org. en. 2018-08-28.
5. UniProt: the universal protein knowledgebase . Nucleic Acids Research . 45 . D1 . D158–D169 . January 2017 . 27899622 . 5210571 . 10.1093/nar/gkw1099 .
6. https://www.ncbi.nlm.nih.gov/gene/5428?ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum Entrez Gene: POLG polymerase (DNA directed), gamma, catalytic subunit
7. Ropp PA, Copeland WC . Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma . Genomics . 36 . 3 . 449–58 . September 1996 . 8884268 . 10.1006/geno.1996.0490 .
8. Graziewicz MA, Longley MJ, Copeland WC . DNA polymerase gamma in mitochondrial DNA replication and repair . Chemical Reviews . 106 . 2 . 383–405 . February 2006 . 16464011 . 10.1021/cr040463d .
9. Giordano C, Powell H, Leopizzi M, De Curtis M, de Curtis M, Travaglini C, Sebastiani M, Gallo P, Taylor RW, d'Amati G . Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to POLG1 mutations . Neurology . 72 . 12 . 1103–5 . March 2009 . 19307547 . 2821839 . 10.1212/01.wnl.0000345002.47396.e1 .
10. Müller-Höcker J, Horvath R, Schäfer S, Hessel H, Müller-Felber W, Kühr J, Copeland WC, Seibel P . Mitochondrial DNA depletion and fatal infantile hepatic failure due to mutations in the mitochondrial polymerase γ (POLG) gene: a combined morphological/enzyme histochemical and immunocytochemical/biochemical and molecular genetic study . Journal of Cellular and Molecular Medicine . 15 . 2 . 445–56 . February 2011 . 19538466 . 3822808 . 10.1111/j.1582-4934.2009.00819.x .
11. Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS, Prolla TA, Loeb LA . Mitochondrial point mutations do not limit the natural lifespan of mice . Nature Genetics . 39 . 4 . 540–3 . April 2007 . 17334366 . 10.1038/ng1988 . 291780 .
12. Web site: 50 binary interactions found for search term POLG . IntAct Molecular Interaction Database . EMBL-EBI . 2018-08-29 .