POLB: A new role of DNA polymerase beta in mitochondrial base excision repair

Kaufman, Brett A.; Houten, Bennett Van

doi:10.1016/j.dnarep.2017.11.002

Cited by 31 publications

(23 citation statements)

References 23 publications

(26 reference statements)

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“…The Polγ holoenzyme is a heterotrimer consisting of two identical accessory subunits (Polγ-B) and one catalytic subunit (Polγ-A), where the accessory subunits enhance the processivity and catalytic function of Polγ-A (Gray and Wong, 1992;Johnson et al, 2000;Carrodeguas et al, 2002;reviewed in Kaguni, 2004). Until recently, Polγ was thought to be the sole polymerase within the mitochondrion that was responsible for both mtDNA replication and repair; however, at least four other DNA polymerases have been noted to play a role in mtDNA maintenance namely, DNA polymerase beta, PrimPol, polymerase theta, and polymerase zeta (Singh et al, 2015;Wisnovsky et al, 2016;Sykora et al, 2017;Bailey et al, 2019;reviewed in Bailey and Doherty, 2017;Kaufman and Van Houten, 2017;Krasich and Copeland, 2017). Until recently, Polγ was thought to be the sole polymerase within the mitochondrion that was responsible for both mtDNA replication and repair; however, at least four other DNA polymerases have been noted to play a role in mtDNA maintenance namely, DNA polymerase beta, PrimPol, polymerase theta, and polymerase zeta (Singh et al, 2015;Wisnovsky et al, 2016;Sykora et al, 2017;Bailey et al, 2019;reviewed in Bailey and Doherty, 2017;Kaufman and Van Houten, 2017;Krasich and Copeland, 2017).…”

Section: Mtdna Replicationtranscription and Repairmentioning

confidence: 99%

“…The DNA helicase, TWINKLE, forms a hexameric donut-shaped structure and is required at the replication fork where it functions ahead of Polγ and unwinds the DNA template for replication (Korhonen et al, 2004;Milenkovic et al, 2013;Fernández-Millán et al, 2015). Until recently, Polγ was thought to be the sole polymerase within the mitochondrion that was responsible for both mtDNA replication and repair; however, at least four other DNA polymerases have been noted to play a role in mtDNA maintenance namely, DNA polymerase beta, PrimPol, polymerase theta, and polymerase zeta (Singh et al, 2015;Wisnovsky et al, 2016;Sykora et al, 2017;Bailey et al, 2019;reviewed in Bailey and Doherty, 2017;Kaufman and Van Houten, 2017;Krasich and Copeland, 2017). mtDNA transcription is still an active area of research as several unknown variables related to initiation, elongation, and termination remain to be elucidated.…”

Section: Mtdna Replicationtranscription and Repairmentioning

confidence: 99%

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Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

120

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Maintenance of the mitochondrial genome is essential for proper cellular function. For this purpose, mitochondrial DNA (mtDNA) needs to be faithfully replicated, transcribed, translated, and repaired in the face of constant onslaught from endogenous and environmental agents. Although only 13 polypeptides are encoded within mtDNA, the mitochondrial proteome comprises over 1500 proteins that are encoded by nuclear genes and translocated to the mitochondria for the purpose of maintaining mitochondrial function. Regulation of mtDNA and mitochondrial proteins by epigenetic changes and post‐translational modifications facilitate crosstalk between the nucleus and the mitochondria and ultimately lead to the maintenance of cellular health and homeostasis. DNA methyl transferases have been identified in the mitochondria implicating that methylation occurs within this organelle; however, the extent to which mtDNA is methylated has been debated for many years. Mechanisms of demethylation within this organelle have also been postulated, but the exact mechanisms and their outcomes is still an active area of research. Mitochondrial dysfunction in the form of altered gene expression and ATP production, resulting from epigenetic changes, can lead to various conditions including aging‐related neurodegenerative disorders, altered metabolism, changes in circadian rhythm, and cancer. Here, we provide an overview of the epigenetic regulation of mtDNA via methylation, long and short noncoding RNAs, and post‐translational modifications of nucleoid proteins (as mitochondria lack histones). We also highlight the influence of xenobiotics such as airborne environmental pollutants, contamination from heavy metals, and therapeutic drugs on mtDNA methylation. Environ. Mol. Mutagen., 60:668–682, 2019. © 2019 Wiley Periodicals, Inc.

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Section: Mtdna Replicationtranscription and Repairmentioning

confidence: 99%

Section: Mtdna Replicationtranscription and Repairmentioning

confidence: 99%

Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

120

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“…In mammals, DNA Polβ is known to be a key enzyme in the nuclear BER pathway, whereas the DNA polymerase involved in the mitochondrial BER pathway appears to be Polγ. However, recently Polβ was identified as a mtDNA polymerase involved in mtDNA maintenance and required for mitochondrial homeostasis in cells from several different mammalian species (Kaufman and Van Houten , Sykora et al ). Interestingly, in the parasite Trypanosoma brucei , a homolog of Polβ was reported to be solely responsible for the repair and replication of mtDNA (Saxowsky et al ).…”

Section: Resultsmentioning

confidence: 99%

DNA repair in plant mitochondria – a complete base excision repair pathway in potato tuber mitochondria

Ferrando

Furlanetto

Gredilla

et al. 2018

Physiologia Plantarum

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Mitochondria are one of the major sites of reactive oxygen species (ROS) production in the plant cell. ROS can damage DNA, and this damage is in many organisms mainly repaired by the base excision repair (BER) pathway. We know very little about DNA repair in plants especially in the mitochondria. Combining proteomics, bioinformatics, western blot and enzyme assays, we here demonstrate that the complete BER pathway is found in mitochondria isolated from potato (Solanum tuberosum) tubers. The enzyme activities of three DNA glycosylases and an apurinic/apyrimidinic (AP) endonuclease (APE) were characterized with respect to Mg dependence and, in the case of the APE, temperature sensitivity. Evidence for the presence of the DNA polymerase and the DNA ligase, which complete the repair pathway by replacing the excised base and closing the gap, was also obtained. We tested the effect of oxidative stress on the mitochondrial BER pathway by incubating potato tubers under hypoxia. Protein carbonylation increased significantly in hypoxic tuber mitochondria indicative of increased oxidative stress. The activity of two BER enzymes increased significantly in response to this oxidative stress consistent with the role of the BER pathway in the repair of oxidative damage to mitochondrial DNA.

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“…Finally, it is noteworthy that mtDNA repair requires DNA polymerases other than DNA polymerase gamma. For instance, it has been shown that DNA polymerase beta and PrimPol, a DNA A c c e p t e d M a n u s c r i p t primase-polymerase, are able to participate to mtDNA repair in addition to their usual role in nuclear DNA repair (Kaufman and Van Houten, 2017;Torregrosa-Muñumer et al, 2017). DNA polymerases theta and zeta could also play a significant role in mtDNA maintenance .…”

Section: Mtdna Repairmentioning

confidence: 99%

Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

Fromenty

2020

Food and Chemical Toxicology

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Mitochondrial DNA (mtDNA) encodes for 13 proteins involved in the oxidative phosphorylation (OXPHOS) process. In liver, genetic or acquired impairment of mtDNA homeostasis can reduce ATP output but also decrease fatty acid oxidation, thus leading to different hepatic lesions including massive necrosis and microvesicular steatosis. Hence, a severe impairment of mtDNA homeostasis can lead to liver failure and death. An increasing number of investigations report that some drugs can induce mitochondrial dysfunction and drug-induced liver injury (DILI) by altering mtDNA homeostasis. Some drugs such as ciprofloxacin, antiretroviral nucleoside reverse-transcriptase inhibitors and tacrine can inhibit hepatic mtDNA replication, thus inducing mtDNA depletion. Drug-induced reduced mtDNA levels can also be the consequence of reactive oxygen speciesmediated oxidative damage to mtDNA, which triggers its degradation by mitochondrial nucleases. Such mechanism is suspected for acetaminophen and troglitazone. Other pharmaceuticals such as linezolid and tetracyclines can impair mtDNA translation, thus selectively reducing the synthesis of the 13 mtDNA-encoded proteins. Lastly, some drugs might alter the mtDNA methylation status but the pathophysiological consequences of such alteration are still unclear. Drug-induced impairment of mtDNA homeostasis is probably under-recognized since preclinical and post-marketing safety studies do not classically investigate mtDNA levels, mitochondrial protein synthesis and mtDNA oxidative damage. 2 A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 2. Main features of the mitochondria 2.1. Structure and main components Mitochondria, whose size is ~1 µm, are intracellular organelles with two membranes (namely the outer and the inner membrane) that surround the matrix. This compartment contains numerous enzymes involved in different key oxidative pathways such as mitochondrial fatty acid oxidation (mtFAO) and pyruvate oxidation via the tricarboxylic acid (TCA) cycle. The matrix also contains the mitochondrial DNA (mtDNA) and all the components (e.g. enzymes and transcription factors) mandatory for its replication, transcription, translation and repair. However, this small genome allows only the synthesis of 13 polypeptides of the mitochondrial respiratory chain (MRC), whereas all other mitochondrial proteins (~1700) are encoded by the nuclear DNA and targeted to mitochondria (Area-Gomez and Schon, 2014; Borst and Grivell, 1981). Notably, mitochondria share different major features with bacteria including size, double-membrane structure, mode of mtDNA transcription and some components of the mtDNA translation machinery (Santini et al., 2017; Schon and Fromenty, 2015). These features are due to the fact that the precursors of mitochondria were bacteria that became endosymbiotic residents of "proto-eukaryotic" cells early in our evolutionary history (Pessayre et al., 2010). 2.2. Production of energy One major role of mitochondria is the production of energy so that these organelles...

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POLB: A new role of DNA polymerase beta in mitochondrial base excision repair

Cited by 31 publications

References 23 publications

Mitochondrial DNA: Epigenetics and environment

Mitochondrial DNA: Epigenetics and environment

DNA repair in plant mitochondria – a complete base excision repair pathway in potato tuber mitochondria

Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

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