Structural highlights
Disease
[DPOG2_HUMAN] Defects in POLG2 are the cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal dominant type 4 (PEOA4) [MIM:610131]. Progressive external ophthalmoplegia is characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.[1]
Function
[DPOG2_HUMAN] Mitochondrial polymerase processivity subunit. Stimulates the polymerase and exonuclease activities, and increases the processivity of the enzyme. Binds to ss-DNA.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Human mitochondrial DNA polymerase (Pol gamma) is the sole replicase in mitochondria. Pol gamma is vulnerable to nonselective antiretroviral drugs and is increasingly associated with mutations found in patients with mitochondriopathies. We determined crystal structures of the human heterotrimeric Pol gamma holoenzyme and, separately, a variant of its processivity factor, Pol gammaB. The holoenzyme structure reveals an unexpected assembly of the mitochondrial DNA replicase where the catalytic subunit Pol gammaA interacts with its processivity factor primarily via a domain that is absent in all other DNA polymerases. This domain provides a structural module for supporting both the intrinsic processivity of the catalytic subunit alone and the enhanced processivity of holoenzyme. The Pol gamma structure also provides a context for interpreting the phenotypes of disease-related mutations in the polymerase and establishes a foundation for understanding the molecular basis of toxicity of anti-retroviral drugs targeting HIV reverse transcriptase.
Structural insight into processive human mitochondrial DNA synthesis and disease-related polymerase mutations.,Lee YS, Kennedy WD, Yin YW Cell. 2009 Oct 16;139(2):312-24. PMID:19837034[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Longley MJ, Clark S, Yu Wai Man C, Hudson G, Durham SE, Taylor RW, Nightingale S, Turnbull DM, Copeland WC, Chinnery PF. Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. Am J Hum Genet. 2006 Jun;78(6):1026-34. Epub 2006 May 4. PMID:16685652 doi:S0002-9297(07)63923-8
- ↑ Lee YS, Kennedy WD, Yin YW. Structural insight into processive human mitochondrial DNA synthesis and disease-related polymerase mutations. Cell. 2009 Oct 16;139(2):312-24. PMID:19837034 doi:10.1016/j.cell.2009.07.050
