POLG

DNA polymerase subunit gamma (POLG or POLG1) is an enzyme that in humans is encoded by the POLG gene.[5] 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).[6]

POLG
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPOLG, MDP1, MIRAS, MTDPS4A, MTDPS4B, PEO, POLG1, POLGA, SANDO, SCAE, polymerase (DNA) gamma, catalytic subunit, DNA polymerase gamma, catalytic subunit, ORF-Y, POLGARF
External IDsOMIM: 174763 MGI: 1196389 HomoloGene: 2016 GeneCards: POLG
Orthologs
SpeciesHumanMouse
Entrez

5428

18975

Ensembl

ENSG00000140521

ENSMUSG00000039176

UniProt

P54098

P54099

RefSeq (mRNA)

NM_002693
NM_001126131

NM_017462
NM_001360095
NM_001360096

RefSeq (protein)

NP_001119603
NP_002684

n/a

Location (UCSC)Chr 15: 89.31 – 89.33 MbChr 7: 79.1 – 79.12 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[7][8] 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.[9][10] 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.[6]

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.[11] 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.[12] 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).[9][10]

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).[6] Pathogenic variants have also been linked with fatal congenital myopathy and gastrointestinal pseudo-obstruction and fatal infantile hepatic failure.[13][14] 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.[15]

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.[16]

References
  1. GRCh38: Ensembl release 89: ENSG00000140521 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000039176 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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.
  6. Entrez Gene: POLG polymerase (DNA directed), gamma, catalytic subunitPublic Domain This article incorporates text from this source, which is in the public domain.
  7. Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Retrieved 2018-08-28.
  8. 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.
  9. "POLG - DNA polymerase subunit gamma-1 - Homo sapiens (Human) - POLG gene & protein". www.uniprot.org. Retrieved 2018-08-28. This article incorporates text available under the CC BY 4.0 license.
  10. "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS, Prolla TA, Loeb LA (April 2007). "Mitochondrial point mutations do not limit the natural lifespan of mice". Nature Genetics. 39 (4): 540–3. doi:10.1038/ng1988. PMID 17334366. S2CID 291780.
  16. "50 binary interactions found for search term POLG". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-29.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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