The DNA polymerase   Y955C disease variant associated with PEO and parkinsonism mediates the incorporation and translesion synthesis opposite 7,8-dihydro-8-oxo-2'-deoxyguanosine

Gra̧ziewicz, Maria A.; Bienstock, Rachelle J.; Copeland, William C.

doi:10.1093/hmg/ddm227

Cited by 85 publications

(77 citation statements)

References 68 publications

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“…The mutation causes Pol␥ incorporation levels to drop below 1% of control activity, yet the life span of these patients is measured not in days or weeks but rather in decades, and the individuals are often symptomless well into adulthood. This and other similar mutations in Pol␥ that cause nearly complete loss of protein activity with adult onset of symptoms (62) suggest the presence of a backup polymerase function in the absence of Pol␥.…”

Section: Discussionsupporting

confidence: 57%

DNA Polymerase Beta Participates in Mitochondrial DNA Repair

Sýkora

Kanno

Akbari

et al. 2017

Molecular and Cellular Biology

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We have detected DNA polymerase beta (Pol␤), known as a key nuclear base excision repair (BER) protein, in mitochondrial protein extracts derived from mammalian tissue and cells. Manipulation of the N-terminal sequence affected the amount of Pol␤ in the mitochondria. Using Pol␤ fragments, mitochondrion-specific protein partners were identified, with the interactors functioning mainly in DNA maintenance and mitochondrial import. Of particular interest was the identification of the proteins TWINKLE, SSBP1, and TFAM, all of which are mitochondrion-specific DNA effectors and are known to function in the nucleoid. Pol␤ directly interacted functionally with the mitochondrial helicase TWINKLE. Human kidney cells with Pol␤ knockout (KO) had higher endogenous mitochondrial DNA (mtDNA) damage. Mitochondrial extracts derived from heterozygous Pol␤ mouse tissue and KO cells had lower nucleotide incorporation activity. Mouse-derived Pol␤ null fibroblasts had severely affected metabolic parameters. Indeed, gene knockout of Pol␤ caused mitochondrial dysfunction, including reduced membrane potential and mitochondrial content. We show that Pol␤ is a mitochondrial polymerase involved in mtDNA maintenance and is required for mitochondrial homeostasis.KEYWORDS DNA polymerase beta, mitochondrial DNA repair, TFAM, base excision repair, mitochondria, mitochondrial health, mutational studies C ellular DNA repair is critical for genomic stability, and the accumulation of DNA damage has been linked to many debilitating human disorders, including accelerated aging, cancer, and neurodegeneration (reviewed in references 1 and 2). Mammalian cells have two genomes, nuclear and mitochondrial, and both have the ability to replicate, accumulate DNA damage, and propagate mutations. The nucleus contains the vast majority of the mammalian genome and has extensive ability to repair complex bulky adducts, double-strand breaks (DSB), single-strand breaks (SSB), and hundreds of chemical DNA modifications. The ability to effectively repair this breadth of damage is achieved through multiple, often overlapping, DNA repair pathways. In contrast, the repair of mitochondrial DNA (mtDNA) is a more limited version of nuclear DNA (nDNA) repair. Mitochondria lack nucleotide excision repair, and the presence of double-strand break repair is debated (recently reviewed in reference 3). Despite the mitochondria having attenuated DNA repair capabilities compared to the nucleus, the accumulation of mtDNA damage is not without consequence. Ineffective mtDNA maintenance is the underlying cause of many human diseases, including Alpers syndrome and chronic progressive external ophthalmoplegia (CPEO) caused by mutations in mitochondrial polymerase gamma (Pol␥) or the TWINKLE helicase (4-6). The accu-

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Section: Discussionsupporting

confidence: 57%

DNA Polymerase Beta Participates in Mitochondrial DNA Repair

Sýkora

Kanno

Akbari

et al. 2017

Molecular and Cellular Biology

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“…Graziewicz et al reported that oxidative DNA lesions block mtDNA replication in vitro, which may result in mtDNA depletion [32]. Depletion of damaged mtDNA could explain the scarcity of oxidative mutations in the AZT mutational spectra.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Damage is not a Major Contributor to AZT-Induced Mitochondrial Mutations

Osborne¹

2015

J AIDS Clin Res

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“…4 With longer disease duration, mtDNA deletions and mutations accumulate, and eventually lead to neuronal death in selectively vulnerable regions in mitochondrial dysfunction such as basal ganglia and cerebellum. 5 In POLG, Y955 specifically plays a critical role in catalysis and fidelity of DNA synthesis, 6 and it is highly conserved in different species. 4,6 POLG mutations can lead to wide-variable clinical presentations.…”

Section: Sectionmentioning

confidence: 99%

“…5 In POLG, Y955 specifically plays a critical role in catalysis and fidelity of DNA synthesis, 6 and it is highly conserved in different species. 4,6 POLG mutations can lead to wide-variable clinical presentations. The age at disease onset varied from 3 months to 66 years.…”

Section: Sectionmentioning

confidence: 99%

Clinical Reasoning: A 58-year-old man with progressive ptosis and walking difficulty

Kuo

Tanji

et al. 2017

Neurology

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A 58-year-old man developed progressive walking difficulty over 10 years. He had normal development and an unremarkable birth history. At age 30, he developed bilateral drooping eyelids with double vision. At age 48, he developed progressive gait unsteadiness, slurred speech, and swallowing difficulty. At age 55, he needed to walk with a cane. He did not have seizures, hearing loss, or memory impairment. He did not have any history of alcohol abuse or exposures to anticonvulsants. His mother has congenital cardiac disease and diabetes mellitus, and his sister has had epilepsy since childhood. His daughter is healthy.On examination, the patient had left exotropia and bilateral ptosis without fatigability. His pupillary reflex to light was normal. He had partial horizontal gaze palsy and lack of upward gaze, which was not overcome by vestibulo-ocular reflex. His saccadic eye movements were slow without nystagmus or square wave jerks. He had scanning speech. He had normal muscle power but decreased vibratory sensation and proprioception in his legs, and his deep tendon reflexes were absent. He had mild bradykinesia and arm rigidity without rest tremor. He had mild dysmetria in bilateral finger-nose-finger, finger chase, and heel-shin slide examinations and he had impaired rapid alternating movements. He had wide-base gait with variable stride length but good heel strike, and he could not perform tandem gait (video at Neurology.org).

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The DNA polymerase Y955C disease variant associated with PEO and parkinsonism mediates the incorporation and translesion synthesis opposite 7,8-dihydro-8-oxo-2'-deoxyguanosine

Cited by 85 publications

References 68 publications

DNA Polymerase Beta Participates in Mitochondrial DNA Repair

DNA Polymerase Beta Participates in Mitochondrial DNA Repair

Oxidative Damage is not a Major Contributor to AZT-Induced Mitochondrial Mutations

Clinical Reasoning: A 58-year-old man with progressive ptosis and walking difficulty

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