Cited by 226DNA Repair MechanismsMitochondrial Function and PathologyEnzyme Structure and Function

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The Mitochondrial p55 Accessory Subunit of Human DNA Polymerase γ Enhances DNA Binding, Promotes Processive DNA Synthesis, and Confers N-Ethylmaleimide Resistance

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Lim, Susan E., Longley, Matthew J., Copeland, William C.·1999·Journal of Biological Chemistry

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Abstract

Human DNA polymerase gamma is composed of a 140-kDa catalytic subunit and a smaller accessory protein variously reported to be 43-54 kDa. Immunoblot analysis of the purified, heterodimeric native human polymerase gamma complex identified the accessory subunit as 55 kDa. We isolated the full-length cDNA encoding a 55-kDa polypeptide, expressed the cDNA in Escherichia coli and purified the 55-kDa protein to homogeneity. Recombinant Hp55 forms a high affinity, salt-stable complex with Hp140 during protein affinity chromatography. Immunoprecipitation, gel filtration, and sedimentation analyses revealed a 190-kDa complex indicative of a native heterodimer. Reconstitution of Hp140.Hp55 raises the salt optimum of Hp140, stimulates the polymerase and exonuclease activities, and increases the processivity of the enzyme by several 100-fold. Similar to Hp140, isolated Hp55 binds DNA with moderate strength and was a specificity for double-stranded primer-template DNA. However, Hp140.Hp55 has a surprisingly high affinity for DNA, and kinetic analyses indicate Hp55 enhances the affinity of Hp140 for primer termini by 2 orders of magnitude. Thus the enhanced DNA binding caused by Hp55 is the basis for the salt tolerance and high processivity characteristic of DNA polymerase gamma. Observation of native DNA polymerase gamma both as an Hp140 monomer and as a heterodimer with Hp55 supports the notion that the two forms act in mitochondrial DNA repair and replication. Additionally, association of Hp55 with Hp140 protects the polymerase from inhibition by N-ethylmaleimide.

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BackgroundInfluential
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Background
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Background
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Background
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Background
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Background
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Mitochondrial Disorders Associated with the Mitochondrial DNA Polymerase g: A Focus on Intersubunit Interactions
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Pharmacogenomics, Toxicogenomics, and DNA Polymerase γ
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Mitochondrial DNA polymerase gamma gene polymorphism is not associated with male infertility
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“It has a single DNA polymerase (Pol γ) [2], mapped on 15q25 responsible for replication and repair of mtDNA.”
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POLG exon 22 skipping induced by different mechanisms in two unrelated cases of Alpers syndrome
de Camaret, B. M., Chassagne, M., Mayençon, M., Padet, S., Crehalet, H., Clerc-Renaud, P., Rouvet, I., Zabot, M. T., Rivier, F., Sarda, P., et al. (2010) · Mitochondrion · doi:10.1016/j.mito.2010.07.011 · Cited by 7
“The 50-kDa POLG2 (or pol γB) subunit encoded by the POLG2 gene (chr 17q21) acts as a processivity factor accelerating polymerisation rate, in addition to increasing affinity of pol γ for DNA (Lim et al., 1999; Farge et al., 2007).”
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Purification, Separation, and Identification of the Human mtDNA Polymerase With and Without Its Accessory Subunit
Longley, M. J., & Copeland, W. C. (2003) · Humana Press eBooks · doi:10.1385/1-59259-284-8:245 · Cited by 7
A new pathogenic POLG variant
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mtDNA replication, maintenance, and nucleoid organization
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Analysis of Translesion DNA Synthesis by the Mitochondrial DNA Polymerase γ
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Functional Analysis of Mutant Mitochondrial DNA Polymerase Proteins Involved in Human Disease
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Copeland, W. C., & Wallace, K. B. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.64219-8 · Cited by 3
The Human Mitochondrial Genome: Mechanisms of Expression and Maintenance
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Copy number variations of the mitochondrial DNA as potential cause of mitochondrial diseases
Mathematisch-naturwissenschaftlichen Fakultät, I. (2010) · Cited by 2
The Human Mitochondrial Genome
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Cardiotoxicity and HIV/AIDS Therapy
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Measurement of kinetic parameters of human platelet DNA polymerase γ
Taanman, J., Heiske, M., & Letellier, T. (2010) · Methods · doi:10.1016/j.ymeth.2010.03.002 · Cited by 2
Mitochondrial Biogenesis and Quality Control
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The disease-causing mutation p.F907I reveals a novel pathogenic mechanism for POLγ-related diseases
Erdinc, D., Macao, B., Valenzuela, S., Lesko, N., Naess, K., Peter, B., Bruhn, H., Wedell, A., Wredenberg, A., & Falkenberg, M. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166786 · Cited by 1
Interference with mitochondrial metabolism could serve as a potential therapeutic strategy for advanced prostate cancer
Wu, C., Zhu, H., Zhang, Y., Ding, L., & Wang, J. (2024) · PLoS ONE · doi:10.1371/journal.pone.0290753 · Cited by 1
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“An accessory subunit was purified and described as a 55kDa protein required for tight DNA binding and processing DNA synthesis (Lim et al., 1999).”
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El espectro clínico de las mutaciones en POLG
Berardo, A. (2011) · Neurología Argentina · doi:10.1016/s1853-0028(11)70023-4 · Cited by 1
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Mitochondrial DNA and RNA Polymerases
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“Holoenzyme exhibits markedly increased processivity of synthesis, reduced exonuclease activity, and elevated 50-dRP lyase activity (Bogenhagen et al. 2001; Carrodeguas et al. 1999; Lim et al. 1999; Longley et al. 1998).”
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Disorders of mitochondrial DNA polymerase: a clinical, biochemical and structural study
Palin, E. (2013) · Työväentutkimus Vuosikirja
Mitochondriale DNA des Menschen
Wissinger, B. (2008) · Springer eBooks · doi:10.1007/978-3-540-69414-4_5
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“The accessory domain of pol γ itself is 55 kDa and is required for tight DNA binding for processive DNA synthesis [2].”
Background

Authors: Lim, S. E., Longley, M. J., & Copeland, W. C.
Affiliations: National Institutes of Health (US)
Corresponding author: Copeland, William C.
ORCID: Longley, Matthew J.
Copeland, William C.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1999-12
Volume: 274
Issue: 53
Pages: 38197-38203
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.274.53.38197
OpenAlex: W2001256046
Cited by: 226
References: 30
Citations by year: 2026: 3 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 3 · 2021: 9 · 2020: 10 · 2019: 3 · 2018: 4 · 2017: 9 · 2016: 6 · 2015: 7 · 2014: 5 · 2013: 7 · 2012: 13
FWCI: 2.97
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 7617 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institute of Environmental Health Sciences
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords: DNA polymerase gamma, heterodimer, DNA binding, processivity, exonuclease activity, salt tolerance, mitochondrial DNA repair, mitochondrial DNA replication, recombinant protein purification
MeSH terms: DNA Polymerase gamma, Base Sequence, DNA, DNA-Directed DNA Polymerase, DNA Replication, Escherichia coli, Ethylmaleimide, Humans, Mitochondria, Molecular Sequence Data, Protein Binding, Recombinant Proteins, Sodium Chloride, DNA Primers, DNA, Complementary, Dimerization, Catalytic Domain

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The Mitochondrial p55 Accessory Subunit of Human DNA Polymerase γ Enhances DNA Binding, Promotes Processive DNA Synthesis, and Confers N-Ethylmaleimide Resistance

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