DNA Polymerase γ in Mitochondrial DNA Replication and Repair

Gra̧ziewicz, Maria A.; Longley, Matthew J.; Copeland, William C.

doi:10.1021/cr040463d

Cited by 250 publications

(229 citation statements)

References 376 publications

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“…2 Mutations in POLG, the gene for the catalytic subunit, cause CPEO, Alper's syndrome, ataxia-neuropathy, Parkinsonism, 2,42 and other heritable conditions. 24 Targeted cardiac TGs were used to define features of cardiac dysfunction and CM, 26 and were applied to explore features of CM in AIDS 43 where nucleoside reverse transcriptase inhibitors (NRTIs) cause mitochondrial dysfunction in the heart.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 It is composed of a catalytic subunit responsible for polymerase and exonuclease activity and a small accessory subunit that enhances binding and processivity. 3 Exonuclease activity allows for proofreading of the growing DNA strand and increases faithful copying of mtDNA.…”

mentioning

confidence: 99%

“…We published biochemical data on the mutant Y955C Pol g protein in CPEO, 2,22,23,25 however the Y955C POLG mutation has not been investigated in transgenic murine models. The effect of human Y955C Pol g on the murine heart was explored using transgenically targeted Y955C POLG driven by the alpha myosin heavy chain promoter (aMyHC).…”

mentioning

confidence: 99%

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Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

Lewis

Day

Kohler

et al. 2007

Laboratory Investigation

116

107

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

Lewis

Day

Kohler

et al. 2007

Laboratory Investigation

116

107

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“…Replication of mtDNA is conducted by DNA polymerase gamma (DNA pol γ). Among the 16 known eukaryotic DNA polymerases, DNA pol γ is the only one to have been detected in mammalian mitochondria (16). According to the strand-asymmetric model, mtDNA replication occurs bi-directionally, being initiated at two spatially and temporally distinct origins of replications OH and OL, for the heavy and light strands respectively (17).…”

Section: Mitochondrial Genomementioning

confidence: 99%

Mitochondrial DNA repair in aging and disease

Druzhyna

Wilson

LeDoux

2008

Mechanisms of Ageing and Development

170

134

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“…The catalytic subunit contains three different domains: a 3 0 -5 0 exonuclease domain, a 'linker' domain and a highly conserved polymerase domain. 1 Mutations in POLG have been identified in severe mtDNA depletion syndromes, such as Alpers syndrome, as well as in mtDNA multiple deletion disorders such as ataxia, chronic progressive external ophthalmoplegia (CPEO), mitochondrial recessive ataxia syndrome, sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) and spinocerebellar ataxia with epilepsy (SCAE) [2][3][4][5] (http://tools.niehs.nih.gov/polg/). Most of these mutations were missense mutations.…”

Section: Introductionmentioning

confidence: 99%

Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort

et al. 2013

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Polymerase gamma (POLG) is the gene most commonly involved in mitochondrial disorders with mitochondrial DNA instability and causes a wide range of diseases with recessive or dominant transmission. More than 170 mutations have been reported. Most of them are missense mutations, although nonsense mutations, splice-site mutations, small deletions and insertions have also been identified. However, to date, only one large-scale rearrangement has been described in a child with Alpers syndrome. Below, we report a large cohort of 160 patients with clinical, molecular and/or biochemical presentation suggestive of POLG deficiency. Using sequencing, we identified POLG variants in 22 patients (18 kindreds) including five novel pathogenic mutations. Two patients with novel mutations had unusual clinical presentation: the first exhibited an isolated ataxic neuropathy and the second was a child who presented with endocrine signs. We completed the sequencing step by quantitative multiplex PCR of short fluorescent fragments (QMPSF) analysis in 37 patients with either only one POLG heterozygous variant or a family history suggesting a dominant transmission. We identified a large intragenic deletion encompassing part of intron 21 and exon 22 of POLG in a child with refractory epilepsia partialis continua. In conclusion, we describe the first large French cohort of patients with POLG mutations, expanding the wide clinical and molecular spectrum observed in POLG disease. We confirm that large deletions in the POLG gene are rare events and we highlight the importance of QMPSF in patients with a single heterozygous POLG mutation, particularly in severe infantile phenotypes.

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DNA Polymerase γ in Mitochondrial DNA Replication and Repair

Cited by 250 publications

References 376 publications

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

Mitochondrial DNA repair in aging and disease

Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort

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