Affinage

POLG

DNA polymerase subunit gamma-1 · UniProt P54098

Length
1239 aa
Mass
139.6 kDa
Annotated
2026-06-10
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POLG encodes the sole DNA polymerase responsible for mitochondrial DNA replication, and its catalytic integrity governs both mtDNA copy number and sequence fidelity (PMID:11431686, PMID:18487244). The enzyme couples a 5'-3' polymerase activity to a 3'-5' proofreading exonuclease: catalytic-domain missense or nonsense mutations cause mtDNA depletion or large-scale deletions, exonuclease-domain mutations specifically erode proofreading and allow accumulation of heteroplasmic point mutations, and processive synthesis requires physical association with the p55 accessory subunit, which the common A467T linker variant disrupts while only mildly reducing intrinsic catalysis (PMID:11431686, PMID:16024923, PMID:14557557, PMID:18487244). Mutations in POLG underlie dominant progressive external ophthalmoplegia and, when catalytic activity is compromised, Alpers syndrome (PMID:11431686, PMID:15122711); the latter can arise from a single functional allele because the partner allele is silenced by nonsense-mediated decay (PMID:16181814). POLG-dependent mtDNA synthesis is limited by mitochondrial dNTP availability (PMID:30848931) and is dynamically controlled by autophagy-dependent nucleotide and ROS homeostasis, with prolonged starvation switching POLG to a degradative exonucleolytic mode (PMID:29519802). POLG abundance is set transcriptionally by ERα binding to its promoter (PMID:32759275), epigenetically by DNA methylation of exon 2 that tunes mtDNA copy number across proliferative and pluripotent states (PMID:25719248), and post-translationally by PARP1, which binds POLG to inhibit mtDNA synthesis and drives its PARylation- and ubiquitination-dependent degradation (PMID:37679327, PMID:40401372). The POLG locus additionally produces POLGARF, a distinct nucleolar/secreted protein translated via CUG initiation from an overlapping reading frame in the 5' leader, in complex with C1QBP (PMID:32958672). At the organismal level, loss of POLG fidelity impairs neural and hematopoietic progenitors through redox imbalance (PMID:22225879) and provokes a folate-cycle-linked mitochondrial integrated stress response in muscle (PMID:40057508).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    Established that POLG is the sole replicative polymerase of mitochondria and that its dysfunction underlies a human disease of mtDNA instability, defining the gene's core biological role.

    Evidence Genetic mapping and mutation identification (Y955C in polymerase motif B) in dominant PEO pedigrees

    PMID:11431686

    Open questions at the time
    • Did not biochemically dissect how Y955C alters catalysis
    • Mechanism linking single-mutation polymerase defect to large-scale deletions not resolved
  2. 2003 Medium

    Showed that the proofreading exonuclease domain is required for replication fidelity, separating fidelity control from polymerization.

    Evidence PCR/sequencing of mtDNA from skeletal muscle and fibroblasts of PEO patients with exonuclease-domain mutations

    PMID:14557557

    Open questions at the time
    • Patient-derived correlation rather than reconstituted exonuclease kinetics
    • Did not isolate exonuclease defect from concurrent polymerase effects
  3. 2004 Medium

    Linked catalytic-activity-deficient POLG genotypes to mtDNA depletion and Alpers syndrome, distinguishing depletion from deletion phenotypes.

    Evidence POLG sequencing plus biochemical catalytic activity measurement in patient pedigrees (E873stop/A467T)

    PMID:15122711

    Open questions at the time
    • Contribution of each allele to the deficit not separated in this study
    • Single lab
  4. 2005 High

    Resolved why the common A467T variant is pathogenic — it cripples turnover and abolishes p55 accessory-subunit interaction and processivity stimulation rather than acting through the exonuclease.

    Evidence Multiple orthogonal in vitro assays with purified recombinant A467T enzyme (processivity, immunoprecipitation, proteolysis protection)

    PMID:16024923

    Open questions at the time
    • Structural basis of disrupted accessory-subunit binding not determined
  5. 2005 Medium

    Explained how a compound heterozygous genotype produces disease through mono-allelic expression, with the nonsense allele degraded by NMD.

    Evidence Western blot and RT-PCR of POLG transcripts in E873stop/A467T patient fibroblasts

    PMID:16181814

    Open questions at the time
    • Generality of NMD-driven mono-allelic expression across other POLG genotypes untested
  6. 2007 Medium

    Distinguished the replication-stalling signature of POLG catalytic mutants from that of the Twinkle helicase, placing POLG within strand-asynchronous mtDNA replication.

    Evidence Expression of catalytic POLG mutants in human cells with analysis of replication intermediates

    PMID:17452351

    Open questions at the time
    • Did not define the molecular trigger of lagging-strand delay
    • Single lab
  7. 2008 Medium

    Defined the genotype-function rule that depletion requires a catalytic-domain or nonsense lesion, whereas two linker mutations preserve copy number.

    Evidence mtDNA quantification across 24 patient fibroblast genotypes

    PMID:18487244

    Open questions at the time
    • Correlative; mechanistic basis of linker-only tolerance not biochemically tested
  8. 2011 High

    Provided a mechanistically informative negative control by showing G517V retains activity, p55 interaction and DNA binding, refining variant pathogenicity criteria.

    Evidence Purified recombinant G517V biochemical assays (polymerase activity, accessory-subunit interaction, DNA binding)

    PMID:21856450

    Open questions at the time
    • Behavior in compound-heterozygous context not addressed
  9. 2012 High

    Connected POLG proofreading loss to stem/progenitor cell dysfunction via redox imbalance, extending mtDNA fidelity to tissue homeostasis.

    Evidence PolgA mutator mouse with NSC/HPC assays and N-acetyl-L-cysteine rescue

    PMID:22225879

    Open questions at the time
    • Precise ROS source and downstream signaling not pinpointed
  10. 2014 Medium

    Demonstrated that heterozygous proofreading deficiency produces age- and tissue-specific mtDNA deletions and motor dysfunction without depletion or point-mutation load.

    Evidence Polg D257A knock-in mice with rotarod testing and tissue mtDNA deletion/point-mutation analysis

    PMID:25540805

    Open questions at the time
    • Mechanism converting proofreading loss to deletions rather than point mutations unresolved
  11. 2015 Medium

    Identified epigenetic methylation at POLG exon 2 as a regulator of mtDNA copy number tied to proliferation and differentiation state.

    Evidence MeDIP/hMeDIP, mtDNA qPCR, and 5-azacytidine demethylation across cancer and pluripotent cells

    PMID:25719248

    Open questions at the time
    • Enzymes setting/erasing the exon-2 mark not identified
    • Single lab
  12. 2018 High

    Revealed that POLG operates in two opposing modes — synthetic versus exonucleolytic degradation — governed by autophagy-dependent nucleotide and ROS homeostasis during starvation.

    Evidence Yeast autophagy mutants with mtDNA copy number, respiration, and nucleotide pool measurements

    PMID:29519802

    Open questions at the time
    • Whether the same starvation switch operates in mammalian cells not shown here
  13. 2019 Medium

    Showed that physiological dNTP concentration rate-limits POLG-mediated mtDNA repopulation, and that supplementation boosts copy number without sacrificing fidelity.

    Evidence Deoxyribonucleoside supplementation in quiescent patient fibroblasts with dNTP and deletion/mutation analysis

    PMID:30848931

    Open questions at the time
    • Did not test fidelity effects in proofreading-mutant backgrounds
  14. 2020 Medium

    Established transcriptional control of POLG by ERα, linking nuclear hormone signaling to mtDNA maintenance in adipose tissue.

    Evidence ChIP for ERα at the Polg1 promoter plus adipose-selective Esr1 knockout mice

    PMID:32759275

    Open questions at the time
    • Direct ERα regulation of human POLG in non-adipose tissues untested
  15. 2020 High

    Uncovered POLGARF, an overlapping CUG-initiated protein from the POLG leader with nucleolar localization, C1QBP interaction, and regulated secretion, expanding the locus's coding capacity.

    Evidence CUG-initiation reporter assays, live imaging, Co-IP with C1QBP, secretion assays, ribosome profiling, phylogenetics

    PMID:32958672

    Open questions at the time
    • Physiological function of the secreted POLGARF fragment not defined
    • Relationship between POLGARF and pol gamma activity unknown
  16. 2020 Medium

    Identified post-transcriptional control of POLG mRNA stability via an OIP5-AS1/HuR scaffold, coupling lncRNA regulation to mitochondrial integrity in lens cells.

    Evidence RIP-qPCR for OIP5-AS1/HuR/POLG mRNA plus POLG knockdown/overexpression with JC-1 and ROS readouts

    PMID:33006594

    Open questions at the time
    • Generality beyond lens epithelial cells unaddressed
  17. 2023 Medium

    Showed PARP1 relocalizes to mitochondria and directly binds and inhibits POLG-mediated mtDNA synthesis, defining a post-translational brake on replication.

    Evidence PARP1/POLG Co-IP, PARP1 knockdown, mitochondrial gene-expression and respiration readouts in VSMCs

    PMID:37679327

    Open questions at the time
    • Single Co-IP without structural mapping of the interaction
    • Direct vs indirect inhibition not fully separated
  18. 2025 Medium

    Extended PARP1 regulation to PARylation- and ubiquitination-dependent POLG degradation driving ferroptosis and vascular calcification, linking POLG turnover to disease.

    Evidence PARP1 KO mice, POLG overexpression/knockdown in vivo, and IP for POLG PARylation and ubiquitination

    PMID:40401372

    Open questions at the time
    • E3 ligase mediating POLG ubiquitination not identified
    • Single lab
  19. 2025 Medium

    Connected muscle POLG dysfunction to the mitochondrial integrated stress response and a specific folate-cycle metabolite depletion, a novel metabolic axis of mitochondrial disease.

    Evidence Inducible muscle-specific PolG mutant mice with metabolomics and mtISR pathway profiling

    PMID:40057508

    Open questions at the time
    • Causal role of 5,10-methenyl-THF depletion in pathology not tested by rescue

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers — dNTP supply, autophagy, ERα transcription, exon-2 methylation, and PARP1-driven PTMs — are integrated to set POLG activity and mtDNA copy number in different tissues remains unresolved.
  • No unified model coordinating transcriptional, post-transcriptional, and post-translational POLG control
  • Physiological role of POLGARF relative to pol gamma undefined
  • Structural basis of disease-mutation effects on the holoenzyme not solved within this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 5 GO:0140657 ATP-dependent activity 2 GO:0003677 DNA binding 1
Localization
GO:0005739 mitochondrion 4 GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-69306 DNA Replication 3 R-HSA-73894 DNA Repair 2
Partners
C1QBPESR1PARP1PKM2POLG2
Complex memberships
pol gamma holoenzyme (POLG–p55/POLG2)

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 POLG encodes the only DNA polymerase responsible for mtDNA replication; heterozygous missense mutation Y955C in the polymerase motif B causes dominant progressive external ophthalmoplegia with accumulation of large-scale mtDNA deletions, establishing POLG as the sole replicative polymerase in mitochondria. Genetic mapping, sequencing, and identification of mutations in patient pedigrees Nature genetics High 11431686
2004 Homozygous Glu873Stop mutation in POLG exon 17 (upstream of polymerase domain) combined with Ala467Thr substitution in exon 7 (linker region) causes deficiency in mitochondrial DNA polymerase gamma catalytic activity, leading to mtDNA depletion and Alpers syndrome. POLG gene sequencing in patient pedigrees, biochemical characterization of catalytic activity deficiency Annals of neurology Medium 15122711
2005 The common A467T mutation in POLG reduces DNA polymerase activity to ~4% of wild-type, primarily via a 6-fold reduction in kcat with minimal effect on exonuclease function, and disrupts physical association with the 55-kDa accessory subunit (p55), abolishing processivity stimulation by the accessory subunit. In vitro biochemical assays (processivity, heat inactivation, N-ethylmaleimide protection, thermolysin digestion, immunoprecipitation) with purified recombinant A467T mutant enzyme The Journal of biological chemistry High 16024923
2003 Mutations in the exonuclease domain of POLG1 reduce its proofreading 3'-5' exonuclease activity, resulting in accumulation of heteroplasmic mtDNA point mutations in skeletal muscle and fibroblasts, demonstrating that POLG's exonuclease domain is required for mtDNA fidelity. Large-scale screening of mtDNA molecules from skeletal muscle by PCR and sequencing in PEO patients with POLG1 exonuclease domain mutations Neurology Medium 14557557
2007 Expression of catalytically deficient POLG1 mutants in human cell culture causes severe mtDNA replication stalling and copy number reduction, but still displays delayed lagging-strand synthesis characteristic of strand-asynchronous replication, whereas Twinkle mutant stalling results in fully double-stranded DNA intermediates. Expression of catalytic mutants of POLG1 in human cell culture, analysis of replication intermediates Nucleic acids research Medium 17452351
2008 mtDNA depletion in patient fibroblasts requires at least one allele with a missense mutation in a catalytic domain (polymerase or exonuclease) or a nonsense mutation; patients with two linker-region mutations only show normal mtDNA content, demonstrating that catalytic domain integrity is specifically required for mtDNA maintenance. Cellular mtDNA content measurement in fibroblasts from 24 patients with defined POLG1 genotypes; mosaic depletion patterns in culture Human molecular genetics Medium 18487244
2011 The G517V substitution in POLG retains 80-90% of wild-type DNA polymerase activity in vitro and maintains functional interaction with the p55 accessory subunit and near-normal DNA binding, indicating this variant is unlikely to be pathogenic by itself. Biochemical analysis of purified recombinant human DNA polymerase γ G517V protein: polymerase activity assays, accessory subunit interaction, DNA binding Mitochondrion High 21856450
2012 MtDNA mutagenesis from defective POLG exonuclease activity leads to dysfunction of neural stem cells (NSC) and hematopoietic progenitor cells (HPC) early in development, with NSC showing decreased self-renewal and HPCs showing abnormal lineage differentiation; N-acetyl-L-cysteine treatment rescued both abnormalities, implicating subtle ROS/redox changes as the mechanism. PolgA mutator mouse model: in vitro NSC self-renewal assays, in vivo NSC quantification, HPC lineage analysis, N-acetyl-L-cysteine rescue experiments Cell metabolism High 22225879
2005 Transcripts of POLG bearing the E873stop premature termination codon undergo nonsense-mediated decay and nonsense-associated alternative splicing, resulting in >95% of functional POLG mRNA being derived from the A467T allele, demonstrating that mono-allelic POLG expression can cause Alpers syndrome. Western blot, RT-PCR analysis of POLG transcripts in patient fibroblasts with E873stop/A467T genotype DNA repair Medium 16181814
2018 In starving yeast cells, POLG (mtDNA polymerase γ) continuously synthesizes mtDNA, but this synthesis is inhibited by nucleotide insufficiency and elevated mitochondria-derived ROS when autophagy is impaired; after prolonged starvation, POLG's 3'-5' exonuclease activity degrades mtDNA, causing quantitative mtDNA instability and irreversible respiratory dysfunction in autophagy-deficient cells. Yeast genetics (autophagy mutants), mtDNA copy number measurement, respiratory function assays, nucleotide pool measurements The Journal of cell biology High 29519802
2020 A CUG triplet in the 5' leader of POLG mRNA initiates translation of a conserved 260-codon overlapping reading frame (POLGARF) with ~60-70% efficiency relative to AUG; unprocessed POLGARF localizes to nucleoli with its interacting partner C1QBP, and serum stimulation causes rapid cleavage and secretion of a POLGARF C-terminal fragment, suggesting a role in extracellular signaling. Reporter assays for CUG initiation efficiency, subcellular localization (live imaging), Co-IP with C1QBP, serum stimulation and secretion assays, ribosome profiling, phylogenetic analysis Proceedings of the National Academy of Sciences of the United States of America High 32958672
2020 ERα (ESR1/Esr1) binds the POLG1 (Polg1) promoter in 3T3L1 adipocytes, directly controlling POLG1 expression; adipose-selective Esr1 deletion reduces Polg1 expression and causes mitochondrial dysfunction in white and brown adipocytes. Chromatin immunoprecipitation (ChIP) assay for ERα binding to Polg1 promoter; adipose-selective Esr1 knockout mice; measurement of mtDNA content and mitochondrial function Science translational medicine Medium 32759275
2023 PARP1 translocates from the nucleus to mitochondria upon lactate stimulation in VSMCs, directly binds POLG and inhibits POLG-mediated mitochondrial DNA synthesis, leading to downregulation of mitochondria-encoded genes and impaired oxidative phosphorylation; PARP1 knockdown partially reverses this mtDNA replication impairment. Co-immunoprecipitation (Co-IP) of PARP1 and POLG, PARP1 knockdown, measurement of mitochondrial gene expression and respiration in VSMC coculture model Cell death & disease Medium 37679327
2025 PARP1-mediated PARylation of POLG in calcified VSMCs triggers ubiquitination-dependent POLG degradation, leading to mitochondrial dysfunction and activation of Adora2a/Rap1 signaling that induces VSMC ferroptosis and promotes vascular calcification; PARP1 inhibition restores POLG levels and mitigates calcification. RNA-sequencing, POLG overexpression and AAV9-sh-POLG knockdown in vivo, PARP1 KO mice (Parp1flox/flox Tagln Cre+), immunoprecipitation for PARylation and ubiquitination of POLG Arteriosclerosis, thrombosis, and vascular biology Medium 40401372
2019 Increasing mitochondrial dNTP pools via deoxyribonucleoside supplementation promotes mtDNA repopulation in POLG-deficient human fibroblasts without compromising POLG fidelity (no increase in deletions or point mutations detected), demonstrating that physiological dNTP concentration limits POLG-mediated mtDNA replication rate. mtDNA copy number recovery assay in quiescent patient fibroblasts following ethidium bromide depletion, dNTP pool measurement, deletion/mutation analysis FASEB journal Medium 30848931
2021 POLG binds to PKM2 by co-immunoprecipitation and affects Tyr105-site phosphorylation of PKM2, thereby interfering with glycolysis in gastric cancer cells; POLG silencing increases glycolytic rate and tumor proliferation in vitro and in vivo. Co-immunoprecipitation (Co-IP) of PolG and PKM2, lentiviral silencing, glycolysis functional assays, xenograft tumor growth Cancer management and research Low 33623435
2020 In lens epithelial cells, the lncRNA OIP5-AS1 acts via HuR as a scaffold to mediate decay of POLG mRNA; POLG depletion decreases mtDNA copy number and mitochondrial membrane potential and increases ROS, sensitizing cells to apoptosis. POLG overexpression reverses these effects. Ribonucleoprotein immunoprecipitation-qPCR (RIP-qPCR) for OIP5-AS1/HuR/POLG mRNA interaction; POLG overexpression and knockdown; JC-1 staining and ROS measurement Investigative ophthalmology & visual science Medium 33006594
2025 Muscle-specific inducible POLG mutation causes rapid mitochondrial dysfunction and muscular degeneration, with robust activation of the mitochondrial integrated stress response (mtISR) and striking depletion of the folate cycle metabolite 5,10-methenyl-THF, identifying imbalanced folate intermediates as a novel pathology linking the mtISR and mitochondrial disease. Inducible tissue-specific PolG mutant mouse model, detailed molecular profiling, metabolomics, mtISR pathway analysis Nature communications Medium 40057508
2014 Heterozygous Polg D257A knock-in mice (proofreading-deficient) accumulate multiple mtDNA deletions in an age-dependent and tissue-specific manner in muscles and brain, leading to motor dysfunction, without significant accumulation of point mutations or mtDNA depletion. Rotarod behavioral testing, tissue-specific mtDNA deletion analysis by PCR, point mutation quantification in heterozygous knock-in mice Annals of clinical and translational neurology Medium 25540805
2015 DNA methylation at exon 2 of POLG (POLGA) regulates mtDNA copy number: highly proliferative cancer and pluripotent cells are heavily methylated at exon 2 with low mtDNA copy number; demethylation (via 5-azacytidine treatment) increases POLG expression and mtDNA copy number, demonstrating epigenetic regulation of POLG controls mtDNA levels and cellular differentiation. Immunoprecipitation of 5mC and 5hmC (MeDIP/hMeDIP), quantitative PCR for mtDNA copy number, 5-azacytidine treatment, cancer cell differentiation assays Cell death & disease Medium 25719248

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature genetics 638 11431686
2004 POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Annals of neurology 325 15122711
2019 POLG-related disorders and their neurological manifestations. Nature reviews. Neurology 313 30451971
2008 Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Human mutation 223 18546365
2004 POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology 209 15477547
2012 Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell metabolism 193 22225879
2010 Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology (Baltimore, Md.) 158 21038416
2008 DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. Biochimica et biophysica acta 127 19010300
2007 Expression of catalytic mutants of the mtDNA helicase Twinkle and polymerase POLG causes distinct replication stalling phenotypes. Nucleic acids research 125 17452351
2003 Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. European journal of human genetics : EJHG 125 12825077
2003 Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology 123 12707443
2008 POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection. Brain : a journal of neurology 118 18238797
2005 The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. The Journal of biological chemistry 114 16024923
2020 Estrogen receptor α controls metabolism in white and brown adipocytes by regulating Polg1 and mitochondrial remodeling. Science translational medicine 99 32759275
2005 POLG mutations and Alpers syndrome. Annals of neurology 97 15929042
2015 Mitochondrial DNA copy number is regulated by DNA methylation and demethylation of POLGA in stem and cancer cells and their differentiated progeny. Cell death & disease 96 25719248
2013 Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harbor perspectives in biology 96 23545419
2003 POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. Human mutation 81 14635118
2010 The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods (San Diego, Calif.) 77 20558295
2006 POLG1 mutations associated with progressive encephalopathy in childhood. Journal of neuropathology and experimental neurology 74 16896309
2009 The unfolding clinical spectrum of POLG mutations. Journal of medical genetics 67 19578034
2004 Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Human reproduction (Oxford, England) 67 14688158
2016 Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review. Epilepsia 65 27554452
2007 Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism. Archives of neurology 65 17420318
2008 Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus. Epilepsia 64 18294203
2006 Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations. European journal of pediatrics 61 16957900
2018 Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation. The Journal of cell biology 54 29519802
2003 Remarkable infidelity of polymerase gammaA associated with mutations in POLG1 exonuclease domain. Neurology 53 14557557
2011 Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations. Journal of neurology 52 21993618
2008 Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations. Human molecular genetics 52 18487244
2006 Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population. Archives of neurology 51 16401742
2012 Characterizing POLG ataxia: clinics, electrophysiology and imaging. Cerebellum (London, England) 49 22528963
2020 Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations. EMBO molecular medicine 48 32840960
2004 The clinical significance of the POLG gene polymorphism in male infertility. The Journal of clinical endocrinology and metabolism 48 15356024
2015 Evidence for polymerase gamma, POLG1 variation in reduced mitochondrial DNA copy number in Parkinson's disease. Parkinsonism & related disorders 45 25585994
2011 POLG1-related and other "mitochondrial Parkinsonisms": an overview. Journal of molecular neuroscience : MN 45 21221844
2010 POLG1 polyglutamine tract variants associated with Parkinson's disease. Neuroscience letters 44 20399836
2016 A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease. PloS one 42 26735972
2010 Mitochondrial DNA depletion and its correlation with TFAM, TFB1M, TFB2M and POLG in human diffusely infiltrating astrocytomas. Mitochondrion 42 20643228
2011 POLG1 manifestations in childhood. Neurology 41 21357833
2020 Unusually efficient CUG initiation of an overlapping reading frame in POLG mRNA yields novel protein POLGARF. Proceedings of the National Academy of Sciences of the United States of America 40 32958672
2014 Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts. Molecular genetics and metabolism 40 24725338
2009 Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. Journal of medical genetics 39 19251978
2009 Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1). Biochimica et biophysica acta 37 19748572
2005 Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers syndrome. DNA repair 36 16181814
2017 Pathogenicity in POLG syndromes: DNA polymerase gamma pathogenicity prediction server and database. BBA clinical 34 28480171
2014 POLG1-related levodopa-responsive parkinsonism. Clinical neurology and neurosurgery 34 25203713
2023 Exploring a new mechanism between lactate and VSMC calcification: PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis. Cell death & disease 33 37679327
2012 Hypertrophic olivary degeneration on magnetic resonance imaging in mitochondrial syndromes associated with POLG and SURF1 mutations. Journal of neurology 33 22729384
2004 Analysis of the trinucleotide CAG repeat from the DNA polymerase gamma gene (POLG) in patients with Parkinson's disease. Neuroscience letters 33 15694274
2022 Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse. Aging cell 32 35993394
2013 Behavioral and metabolic characterization of heterozygous and homozygous POLG mutator mice. Mitochondrion 32 23542163
2009 Rare autosomal dominant POLG1 mutation in a family with metabolic strokes, posterior column spinal degeneration, and multi-endocrine disease. Journal of child neurology 32 19815814
2010 POLG1 variations presenting as multiple sclerosis. Archives of neurology 31 20837861
2014 A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity. Journal of neurology, neurosurgery, and psychiatry 29 25118206
2011 Molecular and biochemical characterisation of a novel mutation in POLG associated with Alpers syndrome. BMC neurology 29 21235791
2008 Parkinsonism associated with the homozygous W748S mutation in the POLG1 gene. Parkinsonism & related disorders 29 18321754
2020 Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon. BMC genetics 28 32138667
2010 POLG, but not PEO1, is a frequent cause of cerebellar ataxia in Central Europe. Movement disorders : official journal of the Movement Disorder Society 28 20803511
2010 Variations of the CAG trinucleotide repeat in DNA polymerase γ (POLG1) is associated with Parkinson's disease in Sweden. Neuroscience letters 27 20826197
2021 Nicotinamide Riboside and Metformin Ameliorate Mitophagy Defect in Induced Pluripotent Stem Cell-Derived Astrocytes With POLG Mutations. Frontiers in cell and developmental biology 26 34631714
2010 Is it ADEM, POLG, or both? Archives of neurology 26 20385918
2017 Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder. Psychiatry and clinical neurosciences 25 27987238
2011 Alpers syndrome with mutations in POLG: clinical and investigative features. Pediatric neurology 25 22000311
2010 A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes. Archives of neurology 25 20142534
2019 Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene. Acta neuropathologica communications 24 31843010
2011 Novel POLG splice site mutation and optic atrophy. Archives of neurology 24 21670405
2020 N-acetylcysteine amide ameliorates mitochondrial dysfunction and reduces oxidative stress in hiPSC-derived dopaminergic neurons with POLG mutation. Experimental neurology 23 33264635
2019 POLG R964C and GBA L444P mutations in familial Parkinson's disease: Case report and literature review. Brain and behavior 23 30941926
2015 Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties. PloS one 23 26468652
2020 Long Noncoding RNA OIP5-AS1 Promotes Cell Apoptosis and Cataract Formation by Blocking POLG Expression Under Oxidative Stress. Investigative ophthalmology & visual science 22 33006594
2019 Increased dNTP pools rescue mtDNA depletion in human POLG-deficient fibroblasts. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 30848931
2006 POLG1, C10ORF2, and ANT1 mutations are uncommon in sporadic progressive external ophthalmoplegia with multiple mitochondrial DNA deletions. Neurology 22 16682683
2021 Efficient clofilium tosylate-mediated rescue of POLG-related disease phenotypes in zebrafish. Cell death & disease 21 33469036
2012 Number of CAG repeats in POLG1 and its association with Parkinson disease in the Norwegian population. Mitochondrion 21 22963882
2006 A new POLG1 mutation with peo and severe axonal and demyelinating sensory-motor neuropathy. Journal of neurology 21 16715201
2015 The in cis T251I and P587L POLG1 base changes: description of a new family and literature review. Neuromuscular disorders : NMD 20 25660390
2015 MitoRCA-seq reveals unbalanced cytocine to thymine transition in Polg mutant mice. Scientific reports 20 26212336
2014 Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions. Annals of clinical and translational neurology 20 25540805
2011 Biochemical analysis of the G517V POLG variant reveals wild-type like activity. Mitochondrion 20 21856450
2023 Miriplatin-loaded liposome, as a novel mitophagy inducer, suppresses pancreatic cancer proliferation through blocking POLG and TFAM-mediated mtDNA replication. Acta pharmaceutica Sinica. B 19 37969736
2020 Hallmarks of frailty and osteosarcopenia in prematurely aged PolgA(D257A/D257A) mice. Journal of cachexia, sarcopenia and muscle 19 32596975
2017 Novel POLG mutations and variable clinical phenotypes in 13 Italian patients. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 18 28130605
2016 Pure Progressive Ataxia and Palatal Tremor (PAPT) Associated with a New Polymerase Gamma (POLG) Mutation. Cerebellum (London, England) 18 26607151
2017 Speech and swallowing abnormalities in adults with POLG associated ataxia (POLG-A). Mitochondrion 17 28634151
2012 Association of mitochondrial DNA polymerase γ gene POLG1 polymorphisms with parkinsonism in Chinese populations. PloS one 17 23251356
2022 The Absence of Parkin Does Not Promote Dopamine or Mitochondrial Dysfunction in PolgAD257A/D257A Mitochondrial Mutator Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 36280265
2018 Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer. International journal of cancer 16 29341116
2025 Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle. Nature communications 15 40057508
2021 PolG Inhibits Gastric Cancer Glycolysis and Viability by Suppressing PKM2 Phosphorylation. Cancer management and research 15 33623435
2018 Specific EEG markers in POLG1 Alpers' syndrome. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 15 30103161
2011 Recurrent major depression, ataxia, and cardiomyopathy: association with a novel POLG mutation? Neuropsychiatric disease and treatment 15 21654874
2010 POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype. BMC neurology 15 20438629
2016 Unique quadruple immunofluorescence assay demonstrates mitochondrial respiratory chain dysfunction in osteoblasts of aged and PolgA(-/-) mice. Scientific reports 14 27553587
2025 PARylation of POLG Mediated by PARP1 Accelerates Ferroptosis-Induced Vascular Calcification via Activating Adora2a/Rap1 Signaling. Arteriosclerosis, thrombosis, and vascular biology 13 40401372
2019 Novel POLG mutation in a patient with early-onset parkinsonism, progressive external ophthalmoplegia and optic atrophy. The International journal of neuroscience 13 31613174
2018 Identification of the first homozygous POLG mutation causing non-syndromic ovarian dysfunction. Climacteric : the journal of the International Menopause Society 13 29992832
2015 The spectrum of epilepsy caused by POLG mutations. Acta neurologica Belgica 13 26104464
2014 Myocerebrohepatopathy spectrum disorder due to POLG mutations: A clinicopathological report. Brain & development 13 25466440
2013 Novel polymerase gamma (POLG1) gene mutation in the linker domain associated with parkinsonism. BMC neurology 13 23865558

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