scholarly journals Regulations of mitochondrial DNA repair by poly(ADP-Ribose) Polymerase 1

2020 ◽  
Author(s):  
Geoffrey K. Herrmann ◽  
Y. Whitney Yin
Keyword(s):  
Dna Repair ◽  
Excision Repair ◽  
Dependent Manner ◽  
Physiological Concentration ◽  
Atp Production ◽  
Mtdna Mutations ◽  
Dna Polymerase Gamma ◽  
Repair Activity ◽  
Base Excision ◽  
Parp1 Inhibitors

ABSTRACTFormation of a repair enzyme complex is beneficial to DNA repair. Despite the fact that mitochondrial base excision repair (mtBER) enzymes DNA polymerase gamma (Pol γ) and poly(ADP-ribose) polymerase 1 (PARP1) were found in the same complex, the functional role of the interaction in mtBER has not been characterized. We report studies that PARP1 regulates Pol γ activity during DNA repair in a metabolic cofactor NAD+ (nicotinamide adenosine dinucleotide)-dependent manner. In the absence of NAD+, PARP1 completely inhibits Pol γ, while increasing NAD+ level to physiological concentration enables Pol γ to resume maximum repair activity. Pol γ is PARylated when bound to DNA repair intermediates, and PARylation is essential for Pol γ repair activity. The PARP1 inhibitor Olaparib that abolishes PARP1 catalytic activity suppresses Pol γ gap-filling synthesis at physiological concentrations of NAD+, suggesting inhibiting PARP1 activity would increase mtDNA mutations. Because NAD+ cellular levels are linked to metabolism and to ATP production via oxidative phosphorylation, our results suggest that mtDNA damage repair is correlated with cellular metabolic state and integrity of the respiratory chain. Our results revealed a molecular basis of drug toxicity from prolonged usage of PARP1 inhibitors in treating cardiac dysfunctions

scholarly journals An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III.

1994 ◽  
Vol 14 (1) ◽  
pp. 68-76 ◽  
Author(s):  
K W Caldecott ◽  
C K McKeown ◽  
J D Tucker ◽  
S Ljungquist ◽  
L H Thompson
Keyword(s):  
Dna Repair ◽  
Affinity Chromatography ◽  
Mammalian Cells ◽  
Excision Repair ◽  
Affinity Purification ◽  
Alkylating Agents ◽  
Chinese Hamster ◽  
Dna Ligase ◽  
Base Excision ◽  
Dna Ligase Iii

XRCC1, the human gene that fully corrects the Chinese hamster ovary DNA repair mutant EM9, encodes a protein involved in the rejoining of DNA single-strand breaks that arise following treatment with alkylating agents or ionizing radiation. In this study, a cDNA minigene encoding oligohistidine-tagged XRCC1 was constructed to facilitate affinity purification of the recombinant protein. This construct, designated pcD2EHX, fully corrected the EM9 phenotype of high sister chromatid exchange, indicating that the histidine tag was not detrimental to XRCC1 activity. Affinity chromatography of extract from EM9 cells transfected with pcD2EHX resulted in the copurification of histidine-tagged XRCC1 and DNA ligase III activity. Neither XRCC1 or DNA ligase III activity was purified during affinity chromatography of extract from EM9 cells transfected with pcD2EX, a cDNA minigene that encodes untagged XRCC1, or extract from wild-type AA8 or untransfected EM9 cells. The copurification of DNA ligase III activity with histidine-tagged XRCC1 suggests that the two proteins are present in the cell as a complex. Furthermore, DNA ligase III activity was present at lower levels in EM9 cells than in AA8 cells and was returned to normal levels in EM9 cells transfected with pcD2EHX or pcD2EX. These findings indicate that XRCC1 is required for normal levels of DNA ligase III activity, and they implicate a major role for this DNA ligase in DNA base excision repair in mammalian cells.

Incorporation of 5’,8-cyclo-2’deoxyadenosines by DNA repair polymerases via base excision repair

DNA Repair ◽  
2021 ◽  
pp. 103258
Author(s):  
Pawlos S. Tsegay ◽  
Daniela Hernandez ◽  
Christopher Brache ◽  
Chryssostomos Chatgilialoglu ◽  
Marios G. Krokidis ◽  
...  
Keyword(s):  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Base Excision

scholarly journals Molecular Mechanisms of the Whole DNA Repair System: A Comparison of Bacterial and Eukaryotic Systems

2010 ◽  
Vol 2010 ◽  
pp. 1-32 ◽  
Author(s):  
Rihito Morita ◽  
Shuhei Nakane ◽  
Atsuhiro Shimada ◽  
Masao Inoue ◽  
Hitoshi Iino ◽  
...  
Keyword(s):  
Dna Repair ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Thermus Thermophilus ◽  
Repair System ◽  
System A ◽  
Recombination Repair ◽  
Repair Mechanisms ◽  
Repair Pathways ◽  
Base Excision

DNA is subjected to many endogenous and exogenous damages. All organisms have developed a complex network of DNA repair mechanisms. A variety of different DNA repair pathways have been reported: direct reversal, base excision repair, nucleotide excision repair, mismatch repair, and recombination repair pathways. Recent studies of the fundamental mechanisms for DNA repair processes have revealed a complexity beyond that initially expected, with inter- and intrapathway complementation as well as functional interactions between proteins involved in repair pathways. In this paper we give a broad overview of the whole DNA repair system and focus on the molecular basis of the repair machineries, particularly inThermus thermophilusHB8.

scholarly journals Expansion of base excision repair compensates for a lack of DNA repair by oxidative dealkylation in budding yeast

2019 ◽  
Vol 294 (37) ◽  
pp. 13629-13637 ◽  
Author(s):  
Suzanne J. Admiraal ◽  
Daniel E. Eyler ◽  
Michael R. Baldwin ◽  
Emily M. Brines ◽  
Christopher T. Lohans ◽  
...  
Keyword(s):  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Budding Yeast ◽  
Base Excision

scholarly journals Spontaneous Mutagenesis Is Enhanced in Apex Heterozygous Mice

2004 ◽  
Vol 24 (18) ◽  
pp. 8145-8153 ◽  
Author(s):  
Jessica Huamani ◽  
C. Alex McMahan ◽  
Damon C. Herbert ◽  
Robert Reddick ◽  
John R. McCarrey ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Germ Line ◽  
Excision Repair ◽  
Spontaneous Mutant ◽  
Spermatogenic Cells ◽  
Ap Endonuclease ◽  
Repair Activity ◽  
Base Excision ◽  
Mutant Frequency

ABSTRACT Germ line DNA directs the development of the next generation and, as such, is profoundly different from somatic cell DNA. Spermatogenic cells obtained from young adult lacI transgenic mice display a lower spontaneous mutant frequency and greater in vitro base excision repair activity than somatic cells and tissues obtained from the same mice. However, spermatogenic cells from old lacI mice display a 10-fold higher mutant frequency. This increased spontaneous mutant frequency occurs coincidentally with decreased in vitro base excision repair activity for germ cell and testicular extracts that in turn corresponds to a decreased abundance of AP endonuclease. To directly test whether a genetic diminution of AP endonuclease results in increased spontaneous mutant frequencies in spermatogenic cell types, AP endonuclease heterozygous (Apex +/−) knockout mice were crossed with lacI transgenic mice. Spontaneous mutant frequencies were significantly elevated (approximately twofold) for liver and spleen obtained from 3-month-old Apex +/− lacI + mice compared to frequencies from Apex +/+ lacI + littermates and were additionally elevated for somatic tissues from 9-month-old mice. Spermatogenic cells from 9-month-old Apex +/− lacI + mice were significantly elevated twofold compared to levels for 9-month-old Apex +/+ lacI + control mice. These data indicate that diminution of AP endonuclease has a significant effect on spontaneous mutagenesis in somatic and germ line cells.

scholarly journals Impact of hypoxia on DNA repair and genome integrity

Mutagenesis ◽  
2019 ◽  
Vol 35 (1) ◽  
pp. 61-68 ◽  
Author(s):  
Alanna R Kaplan ◽  
Peter M Glazer
Keyword(s):  
Dna Repair ◽  
Cancer Progression ◽  
Base Excision Repair ◽  
Mutation Frequency ◽  
Excision Repair ◽  
Tumour Microenvironment ◽  
Genome Integrity ◽  
Future Directions ◽  
Homology Directed Repair ◽  
Base Excision

Abstract Hypoxia is a hallmark of the tumour microenvironment with profound effects on tumour biology, influencing cancer progression, the development of metastasis and patient outcome. Hypoxia also contributes to genomic instability and mutation frequency by inhibiting DNA repair pathways. This review summarises the diverse mechanisms by which hypoxia affects DNA repair, including suppression of homology-directed repair, mismatch repair and base excision repair. We also discuss the effects of hypoxia mimetics and agents that induce hypoxia on DNA repair, and we highlight areas of potential clinical relevance as well as future directions.

scholarly journals An optimized comet-based in vitro DNA repair assay to assess base and nucleotide excision repair activity

2020 ◽  
Vol 15 (12) ◽  
pp. 3844-3878
Author(s):  
Sona Vodenkova ◽  
Amaya Azqueta ◽  
Andrew Collins ◽  
Maria Dusinska ◽  
Isabel Gaivão ◽  
...  
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Nucleotide Excision ◽  
Repair Activity

scholarly journals Tautomerization-dependent recognition and excision of oxidation damage in base-excision DNA repair

2016 ◽  
Vol 113 (28) ◽  
pp. 7792-7797 ◽  
Author(s):  
Chenxu Zhu ◽  
Lining Lu ◽  
Jun Zhang ◽  
Zongwei Yue ◽  
Jinghui Song ◽  
...  
Keyword(s):  
Dna Repair ◽  
Excision Repair ◽  
Mammalian Genome ◽  
Dna Bases ◽  
Repair Pathway ◽  
Thymine Glycol ◽  
Base Excision ◽  
Oxidation Damage ◽  
Biochemical Analyses ◽  
Base Excision Dna Repair

NEIL1 (Nei-like 1) is a DNA repair glycosylase guarding the mammalian genome against oxidized DNA bases. As the first enzymes in the base-excision repair pathway, glycosylases must recognize the cognate substrates and catalyze their excision. Here we present crystal structures of human NEIL1 bound to a range of duplex DNA. Together with computational and biochemical analyses, our results suggest that NEIL1 promotes tautomerization of thymine glycol (Tg)—a preferred substrate—for optimal binding in its active site. Moreover, this tautomerization event also facilitates NEIL1-catalyzed Tg excision. To our knowledge, the present example represents the first documented case of enzyme-promoted tautomerization for efficient substrate recognition and catalysis in an enzyme-catalyzed reaction.

scholarly journals Dynamic Compartmentalization of Base Excision Repair Proteins in Response to Nuclear and Mitochondrial Oxidative Stress

2008 ◽  
Vol 29 (3) ◽  
pp. 794-807 ◽  
Author(s):  
Lyra M. Griffiths ◽  
Dan Swartzlander ◽  
Kellen L. Meadows ◽  
Keith D. Wilkinson ◽  
Anita H. Corbett ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Intracellular Localization ◽  
Genotoxic Stress ◽  
Mitochondrial Oxidative Stress ◽  
Base Excision

ABSTRACT DNAs harbored in both nuclei and mitochondria of eukaryotic cells are subject to continuous oxidative damage resulting from normal metabolic activities or environmental insults. Oxidative DNA damage is primarily reversed by the base excision repair (BER) pathway, initiated by N-glycosylase apurinic/apyrimidinic (AP) lyase proteins. To execute an appropriate repair response, BER components must be distributed to accommodate levels of genotoxic stress that may vary considerably between nuclei and mitochondria, depending on the growth state and stress environment of the cell. Numerous examples exist where cells respond to signals, resulting in relocalization of proteins involved in key biological transactions. To address whether such dynamic localization contributes to efficient organelle-specific DNA repair, we determined the intracellular localization of the Saccharomyces cerevisiae N-glycosylase/AP lyases, Ntg1 and Ntg2, in response to nuclear and mitochondrial oxidative stress. Fluorescence microscopy revealed that Ntg1 is differentially localized to nuclei and mitochondria, likely in response to the oxidative DNA damage status of the organelle. Sumoylation is associated with targeting of Ntg1 to nuclei containing oxidative DNA damage. These studies demonstrate that trafficking of DNA repair proteins to organelles containing high levels of oxidative DNA damage may be a central point for regulating BER in response to oxidative stress.

scholarly journals Formation of cytosine glycol and 5,6-dihydroxycytosine in deoxyribonucleic acid on treatment with osmium tetroxide

1986 ◽  
Vol 235 (2) ◽  
pp. 531-536 ◽  
Author(s):  
M Dizdaroglu ◽  
E Holwitt ◽  
M P Hagan ◽  
W F Blakely
Keyword(s):  
Dna Repair ◽  
Formic Acid ◽  
Excision Repair ◽  
Dna Lesions ◽  
Gas Chromatography Mass Spectrometry ◽  
Dna Glycosylases ◽  
Thymine Glycol ◽  
Repair Enzymes ◽  
Base Excision

OsO4 selectively forms thymine glycol lesions in DNA. In the past, OsO4-treated DNA has been used as a substrate in studies of DNA repair utilizing base-excision repair enzymes such as DNA glycosylases. There is, however, no information available on the chemical identity of other OsO4-induced base lesions in DNA. A complete knowledge of such DNA lesions may be of importance for repair studies. Using a methodology developed recently for characterization of oxidative base damage in DNA, we provide evidence for the formation of cytosine glycol and 5,6-dihydroxycytosine moieties, in addition to thymine glycol, in DNA on treatment with OsO4. For this purpose, samples of OsO4-treated DNA were hydrolysed with formic acid, then trimethylsilylated and analysed by capillary gas chromatography-mass spectrometry. In addition to thymine glycol, 5-hydroxyuracil (isobarbituric acid), 5-hydroxycytosine and 5,6-dihydroxyuracil (isodialuric acid or dialuric acid) were identified in OsO4-treated DNA. It is suggested that 5-hydroxyuracil was formed by formic acid-induced deamination and dehydration of cytosine glycol, which was the actual oxidation product of the cytosine moiety in DNA. 5-Hydroxycytosine obviously resulted from dehydration of cytosine glycol, and 5,6-dihydroxyuracil from deamination of 5,6-dihydroxycytosine. This scheme was supported by the presence of 5-hydroxyuracil, uracil glycol and 5,6-dihydroxyuracil in OsO4-treated cytosine. Treatment of OsO4-treated cytosine with formic acid caused the complete conversion of uracil glycol into 5-hydroxyuracil. The implications of these findings relative to studies of DNA repair are discussed.

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