POLG

DNA polymerase subunit gamma (POLG or POLG1) is an enzyme that in humans is encoded by the ''POLG'' gene. 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. POLG, the protein encoded by this gene, is a member of the DNA polymerase type-A family. It is a mitochondrion nucleoid with an Mg2+ cofactor and 15 turns, 52 beta strands, and 39 alpha helixes. 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.Entrez Gene: POLG polymerase (DNA directed), gamma, catalytic subunit
/ref> The human ''POLG'' cDNA and gene were cloned and mapped to chromosome band 15q25. 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. 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. 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.

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.

References

Further reading

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External links

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

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DNA replication