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(The kDa mass and amino acid number for POLG were wrong. I've fixed this. See ref 11 of this Wikipedia article.)
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{{Infobox_gene}}
{{Infobox_gene}}
'''DNA polymerase subunit gamma''' is an [[enzyme]] that in humans is encoded by the ''POLG'' [[gene]].<ref name="pmid9465903">{{cite journal | vauthors = Zullo SJ, Butler L, Zahorchak RJ, Macville M, Wilkes C, Merril CR | title = 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) | journal = Cytogenetics and Cell Genetics | volume = 78 | issue = 3-4 | pages = 281–4 | date = Mar 1998 | pmid = 9465903 | pmc =  | doi = 10.1159/000134672 }}</ref>
'''DNA polymerase subunit gamma (POLG or POLG1)''' is an [[enzyme]] that in humans is encoded by the ''POLG'' [[gene]].<ref name="pmid9465903">{{cite journal | vauthors = Zullo SJ, Butler L, Zahorchak RJ, Macville M, Wilkes C, Merril CR | title = 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) | journal = Cytogenetics and Cell Genetics | volume = 78 | issue = 3-4 | pages = 281–4 | date = Mar 1998 | pmid = 9465903 | pmc =  | doi = 10.1159/000134672 }}</ref> 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).<ref name=":1" />
 
== Structure ==
''POLG'' is located on the [[Locus (genetics)|q arm]] of chromosome 15 in position 26.1 and has 23 [[Exon|exons]]. The ''POLG'' gene produces a 140 kDa protein composed of 1239 [[Amino acid|amino acids]].<ref>{{Cite web|url=https://amino.heartproteome.org/web/protein/Q9U208|title=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information|last=Yao|first=Daniel|website=amino.heartproteome.org|access-date=2018-08-28}}</ref><ref>{{cite journal | vauthors = 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 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref> 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⁺|Mg2+]] cofactor and 15 turns, 52 [[Beta sheet|beta strands]], and 39 [[Alpha helix|alpha helixes]].<ref name=":2">{{Cite web|url=https://www.uniprot.org/uniprot/P54098|title=POLG - DNA polymerase subunit gamma-1 - Homo sapiens (Human) - POLG gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-28}}{{CC-notice|cc=by4}}</ref><ref name=":0">{{cite journal | vauthors =  | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158-D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}</ref> 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. <ref name=":1" />


== Function ==
== Function ==


POLG is a gene that codes for the catalytic subunit of the mitochondrial [[DNA polymerase]], called DNA polymerase gamma.<ref>
POLG is a gene that codes for the catalytic subunit of the mitochondrial [[DNA polymerase]], called DNA polymerase gamma.<ref name=":1">[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]{{PD-notice}}</ref> The human ''POLG'' cDNA and gene were cloned and mapped to chromosome band 15q25.<ref>{{cite journal | vauthors = Ropp PA, Copeland WC | title = Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma | journal = Genomics | volume = 36 | issue = 3 | pages = 449–58 | date = September 1996 | pmid = 8884268 | doi = 10.1006/geno.1996.0490 }}</ref>  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.<ref>{{cite journal | vauthors = Graziewicz MA, Longley MJ, Copeland WC | title = DNA polymerase gamma in mitochondrial DNA replication and repair | journal = Chemical Reviews | volume = 106 | issue = 2 | pages = 383–405 | date = February 2006 | pmid = 16464011 | doi = 10.1021/cr040463d }}</ref>  The catalytic subunit contains three enzymatic activities, a DNA polymerase activity, a 3’-5’ exonuclease activity that proofreads misincorporated [[Nucleotide|nucleotides]], and a 5’-dRP [[lyase]] activity required for [[base excision repair]].
[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]</ref> The human ''POLG'' cDNA and gene were cloned and mapped to chromosome band 15q25.<ref>{{cite journal | vauthors = Ropp PA, Copeland WC | title = Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma | journal = Genomics | volume = 36 | issue = 3 | pages = 449–58 | date = Sep 1996 | pmid = 8884268 | doi = 10.1006/geno.1996.0490}}</ref>  In [[eukaryotic]] cells, the [[mitochondrial DNA]] is replicated by DNA polymerase gamma, a trimeric protein complex composed of a catalytic subunit of 140 kDa encoded by the ''POLG'' gene and a dimeric accessory subunit of 55 kDa encoded by the ''[[POLG2]]'' gene.<ref>{{cite journal | vauthors = Graziewicz MA, Longley MJ, Copeland WC | title = DNA polymerase gamma in mitochondrial DNA replication and repair | journal = Chemical Reviews | volume = 106 | issue = 2 | pages = 383–405 | date = Feb 2006 | pmid = 16464011 | doi = 10.1021/cr040463d }}</ref>  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).<ref name=":2" /><ref name=":0" />


== Clinical significance ==
== Clinical significance ==


Mutations in the ''POLG'' gene are associated with several [[mitochondrial diseases]], including [[Alpers' disease]], [[ataxia-neuropathy]] disorders, and dominant and recessive forms of [[progressive external ophthalmoplegia]].   A list of all published mutations in the ''POLG'' coding region and their associated disease can be found at the [http://tools.niehs.nih.gov/polg/ Human DNA Polymerase Gamma Mutation Database].
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).<ref name=":1" /> Pathogenic variants have also been linked with fatal congenital [[myopathy]] and gastrointestinal pseudo-obstruction and fatal infantile [[hepatic failure]].<ref>{{cite journal | vauthors = Giordano C, Powell H, Leopizzi M, De Curtis M, de Curtis M, Travaglini C, Sebastiani M, Gallo P, Taylor RW, d'Amati G | title = Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to POLG1 mutations | journal = Neurology | volume = 72 | issue = 12 | pages = 1103–5 | date = March 2009 | pmid = 19307547 | pmc = 2821839 | doi = 10.1212/01.wnl.0000345002.47396.e1 }}</ref><ref>{{cite journal | vauthors = Müller-Höcker J, Horvath R, Schäfer S, Hessel H, Müller-Felber W, Kühr J, Copeland WC, Seibel P | title = 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 = Journal of Cellular and Molecular Medicine | volume = 15 | issue = 2 | pages = 445–56 | date = February 2011 | pmid = 19538466 | pmc = 3822808 | doi = 10.1111/j.1582-4934.2009.00819.x }}</ref> A list of all published mutations in the ''POLG'' coding region and their associated disease can be found at the [http://tools.niehs.nih.gov/polg/ Human DNA Polymerase Gamma Mutation Database].
 
== Interactions ==
POLG has been shown to have 50 binary [[Protein–protein interaction|protein-protein interactions]] including 32 co-complex interactions. POLG appears to interact with [[POLG2]], [[DLG4|Dlg4]], [[TP53-inducible glycolysis and apoptosis regulator|Tp53]], and [[SOD2|Sod2]].<ref>{{cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=POLG | title = 50 binary interactions found for search term POLG | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-29 }}</ref>
 


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


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[[Category:DNA replication]]
[[Category:DNA replication]]

Revision as of 19:02, 12 December 2018

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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).[2]

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.[3][4] 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.[5][6] 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. [2]

Function

POLG is a gene that codes for the catalytic subunit of the mitochondrial DNA polymerase, called DNA polymerase gamma.[2] 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).[5][6]

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).[2] 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.

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.[11]


References

  1. ↑ Zullo SJ, Butler L, Zahorchak RJ, Macville M, Wilkes C, Merril CR (Mar 1998). "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. doi:10.1159/000134672. PMID 9465903.
  2. ↑ 2.0 2.1 2.2 2.3 Entrez Gene: POLG polymerase (DNA directed), gamma, catalytic subunit This article incorporates text from this source, which is in the public domain.
  3. ↑ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Retrieved 2018-08-28.
  4. ↑ 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 (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  5. ↑ 5.0 5.1 "POLG - DNA polymerase subunit gamma-1 - Homo sapiens (Human) - POLG gene & protein". www.uniprot.org. Retrieved 2018-08-28.File:CC-BY-icon-80x15.png This article incorporates text available under the CC BY 4.0 license.
  6. ↑ 6.0 6.1 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  7. ↑ Ropp PA, Copeland WC (September 1996). "Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma". Genomics. 36 (3): 449–58. doi:10.1006/geno.1996.0490. PMID 8884268.
  8. ↑ Graziewicz MA, Longley MJ, Copeland WC (February 2006). "DNA polymerase gamma in mitochondrial DNA replication and repair". Chemical Reviews. 106 (2): 383–405. doi:10.1021/cr040463d. PMID 16464011.
  9. ↑ Giordano C, Powell H, Leopizzi M, De Curtis M, de Curtis M, Travaglini C, Sebastiani M, Gallo P, Taylor RW, d'Amati G (March 2009). "Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to POLG1 mutations". Neurology. 72 (12): 1103–5. doi:10.1212/01.wnl.0000345002.47396.e1. PMC 2821839. PMID 19307547.
  10. ↑ Müller-Höcker J, Horvath R, Schäfer S, Hessel H, Müller-Felber W, Kühr J, Copeland WC, Seibel P (February 2011). "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. doi:10.1111/j.1582-4934.2009.00819.x. PMC 3822808. PMID 19538466.
  11. ↑ "50 binary interactions found for search term POLG". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-29.

Further reading

  • Graziewicz MA, Longley MJ, Copeland WC (February 2006). "DNA polymerase gamma in mitochondrial DNA replication and repair". Chemical Reviews. 106 (2): 383–405. doi:10.1021/cr040463d. PMID 16464011.
  • Hudson G, Chinnery PF (October 2006). "Mitochondrial DNA polymerase-gamma and human disease". Human Molecular Genetics. 15 Spec No 2: R244–52. doi:10.1093/hmg/ddl233. PMID 16987890.
  • Lestienne P (August 1987). "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. doi:10.1016/0006-291X(87)90767-4. PMID 3619920.
  • Ropp PA, Copeland WC (September 1996). "Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma". Genomics. 36 (3): 449–58. doi:10.1006/geno.1996.0490. PMID 8884268.
  • Lecrenier N, Van Der Bruggen P, Foury F (January 1997). "Mitochondrial DNA polymerases from yeast to man: a new family of polymerases". Gene. 185 (1): 147–52. doi:10.1016/S0378-1119(96)00663-4. PMID 9034326.
  • Walker RL, Anziano P, Meltzer PS (March 1997). "A PAC containing the human mitochondrial DNA polymerase gamma gene (POLG) maps to chromosome 15q25". Genomics. 40 (2): 376–8. doi:10.1006/geno.1996.4580. PMID 9119411.
  • Kapsa RM, Quigley AF, Han TF, Jean-Francois MJ, Vaughan P, Byrne E (October 1998). "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. doi:10.1093/nar/26.19.4365. PMC 147866. PMID 9742236.
  • Spelbrink JN, Toivonen JM, Hakkaart GA, Kurkela JM, Cooper HM, Lehtinen SK, Lecrenier N, Back JW, Speijer D, Foury F, Jacobs HT (August 2000). "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. doi:10.1074/jbc.M000559200. PMID 10827171.
  • Van Goethem G, Dermaut B, Löfgren A, Martin JJ, Van Broeckhoven C (July 2001). "Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions". Nature Genetics. 28 (3): 211–2. doi:10.1038/90034. PMID 11431686.
  • Hirano M, DiMauro S (December 2001). "ANT1, Twinkle, POLG, and TP: new genes open our eyes to ophthalmoplegia". Neurology. 57 (12): 2163–5. doi:10.1212/wnl.57.12.2163. PMID 11756592.
  • Ponamarev MV, Longley MJ, Nguyen D, Kunkel TA, Copeland WC (May 2002). "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. doi:10.1074/jbc.C200100200. PMID 11897778.
  • Nitanai Y, Satow Y, Adachi H, Tsujimoto M (August 2002). "Crystal structure of human renal dipeptidase involved in beta-lactam hydrolysis". Journal of Molecular Biology. 321 (2): 177–84. doi:10.1016/S0022-2836(02)00632-0. PMID 12144777.
  • Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei S, Papadimitriou A, Spelbrink H, Silvestri L, Casari G, Comi GP, Zeviani M (August 2002). "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. doi:10.1002/ana.10278. PMID 12210792.
  • 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 (February 2003). "Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia". Neuromuscular Disorders. 13 (2): 133–42. doi:10.1016/S0960-8966(02)00216-X. PMID 12565911.
  • Jazayeri M, Andreyev A, Will Y, Ward M, Anderson CM, Clevenger W (March 2003). "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. doi:10.1074/jbc.M211730200. PMID 12645575.
  • Garrido N, Griparic L, Jokitalo E, Wartiovaara J, van der Bliek AM, Spelbrink JN (April 2003). "Composition and dynamics of human mitochondrial nucleoids". Molecular Biology of the Cell. 14 (4): 1583–96. doi:10.1091/mbc.E02-07-0399. PMC 153124. PMID 12686611.
  • Agostino A, Valletta L, Chinnery PF, Ferrari G, Carrara F, Taylor RW, Schaefer AM, Turnbull DM, Tiranti V, Zeviani M (April 2003). "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO)". Neurology. 60 (8): 1354–6. doi:10.1212/01.wnl.0000056088.09408.3c. PMID 12707443.
  • Van Goethem G, Schwartz M, Löfgren A, Dermaut B, Van Broeckhoven C, Vissing J (July 2003). "Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy". European Journal of Human Genetics. 11 (7): 547–9. doi:10.1038/sj.ejhg.5201002. PMID 12825077.
  • Zullo SJ, Butler L, Zahorchak RJ, Macville M, Wilkes C, Merril CR (Mar 1998). "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. doi:10.1159/000134672. PMID 9465903.

External links

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