DNA precursor metabolism and genomic stability

Mathews, Christopher K.

doi:10.1096/fj.06-5730rev

Cited by 260 publications

(243 citation statements)

References 123 publications

(130 reference statements)

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“…The leukemic cells assayed here were p53 ¡/¡ and/or pten ¡/¡ , which have intrinsic genomic instability 32,33,46 and are permissive for polyploidisation. 34 The observed increase in aneuploidy induced by Erk5 silencing could result from initial dNTP misincorporation due to nucleotide imbalance, which may produce DNA damage and chromosomal instability, 29 presumably through mitotic nondisjunction. 47 An initial dNTP imbalance during the generation of shErk5 cells could later be compensated for by additional modifications to allow cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…28 The increased death response of shErk5 cells to thymidine was not due to absence of p21 Waf1/Cip1 (supplementary material During DNA replication, the presence of nucleotide imbalance leads to misincorporation, DNA damage and chromosomal instability. 29 Of note, there was an increase in DNA damage (H2AX phosphorylation) in Erk5-depleted cells incubated with thymidine (Figs. 2, 3).…”

Section: Depletion Of Erk5 Is Synergistic With Thymidine In Decreasinmentioning

confidence: 91%

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Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

et al. 2015

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An adequate supply of nucleotides is essential for accurate DNA replication, and inappropriate deoxyribonucleotide triphosphate (dNTP) concentrations can lead to replication stress, a common source of DNA damage, genomic instability and tumourigenesis. Here, we provide evidence that Erk5 is necessary for correct nucleotide supply during erythroid development. Mice with Erk5 knockout in the haematopoietic lineage showed impaired erythroid development in bone marrow, accompanied by altered dNTP levels and increased DNA mutagenesis in erythroid progenitors as detected by exome sequencing. Moreover, Erk5-depleted leukemic Jurkat cells presented a marked sensitivity to thymidine-induced S phase stalling, as evidenced by increased H2AX phosphorylation and apoptosis. The increase in thymidine sensitivity correlated with a higher dTTP/dCTP ratio. These results indicate that Erk5 is necessary to maintain the balance of nucleotide levels, thus preventing dNTP misincorporation and DNA damage in proliferative erythroid progenitors and leukemic Jurkat T cells.

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Section: Discussionmentioning

confidence: 99%

Section: Depletion Of Erk5 Is Synergistic With Thymidine In Decreasinmentioning

confidence: 91%

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

et al. 2015

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“…[1][2][3] These modifications often cause a nucleotide to pair with an alternate partner nucleotide in DNA. 4,5 For example, 8-oxo-dGTP, an oxidized product of dGTP, can pair with adenine as well as cytosine during replication, resulting in a transversion mutation.…”

mentioning

confidence: 99%

“…6 Similar to oxidation, deamination is also a common chemical modification that nucleotides may undergo under physiological conditions. 1,2 In the case of deaminated purine bases, such as hypoxanthine, it is considered that inosine triphosphate pyrophosphatase (ITPase), endonuclease V and hypoxanthine-DNA glycosylase have a role in eliminating the deaminated bases from DNA. [16][17][18][19] Saparbaev and Laval 19 reported that alkylpurine-DNA glycosylases engage in hypoxanthine-DNA glycosylase activity both in Escherichia coli and mammalian cells.…”

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confidence: 99%

ITPase-deficient mice show growth retardation and die before weaning

et al. 2009

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Inosine triphosphate pyrophosphatase (ITPase), the enzyme that hydrolyzes ITP and other deaminated purine nucleoside triphosphates to the corresponding purine nucleoside monophosphate and pyrophosphate, is encoded by the Itpa gene. In this study, we established Itpa knockout (KO) mice and used them to show that ITPase is required for the normal organization of sarcomeres in the heart. Itpa À/À mice died about 2 weeks after birth with features of growth retardation and cardiac myofiber disarray, similar to the phenotype of the cardiac a-actin KO mouse. Inosine nucleotides were found to accumulate in both the nucleotide pool and RNA of Itpa À/À mice. These data suggest that the role of ITPase in mice is to exclude ITP from the ATP pool, and the main target substrate of this enzyme is rITP. Our data also suggest that cardiomyopathy, which is mainly caused by mutations in sarcomeric protein-encoding genes, is also caused by a defect in maintaining the quality of the ATP pool, which is an essential requirement for sarcomere function.

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“…Balanced as well as unbalanced dNTP accumulations are mutagenic; mutation rates and mutational spectra could be influenced by dNTP levels in mitochondria. 16,17 Mice expressing an error-prone form of pol Tel: þ 972 3 5304769; Fax: þ 972 3 5303501; E-mail: bakhanus@yahoo.com Keywords: p53; 3 0 -5 0 exonuclease; DNA polymerase g; mitochondrial DNA; apoptosis Abbreviations: H1299mit, mitochondrial fraction of H1299 cells; HCT116 (p53À/À)mit, mitochondrial fraction of HCT116 (p53À/À) cells; HCT116 (p53 þ / þ )mit, mitochondrial fraction of HCT116 (p53 þ / þ ) cells; LCC2cyt, cytoplasmic fraction of LCC2 cells; mtDNA, mitochondrial DNA; pol g, DNA polymerase g; wtp53, wild-type p53 …”

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confidence: 99%

p53 in mitochondria enhances the accuracy of DNA synthesis

et al. 2008

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Mitochondrial localization of p53 was observed in stressed and unstressed cells. p53 is involved in DNA repair and apoptosis. It exerts physical and functional interactions with mitochondrial DNA and DNA polymerase c (pol c). The functional cooperation of p53 and pol c during DNA synthesis was examined in the mitochondrial fraction of p53-null H1299 cells, as the source of pol c. The results show that p53 may affect the accuracy of DNA synthesis in mitochondria: (1) the excision of a misincorporated nucleotide increases in the presence of (a) recombinant wild-type p53 (wtp53); (b) cytoplasmic fraction of LCC2 cells expressing endogenous wtp53 (but not specifically pre-depleted fraction); (c) cytoplasmic extract of H1299 cells overexpressing wtp53, but not exonuclease-deficient mutant p53-R175H. (2) Mitochondrial extracts of HCT116(p53 þ / þ ) cells display higher exonuclease activity compared with that of HCT116(p53À/À) cells. Addition of exogenous p53 complements the HCT116(p53À/À) mitochondrial extract mispair excision. Furthermore, the misincorporation was lower in the mitochondrial fraction of HCT116(p53 þ / þ ) cells as compared with that of HCT116(p53À/À) cells. The tumor suppressor protein p53 represents a central factor for the maintenance of genome stability and for the suppression of cancer. 1 p53 is present at low levels in unstressed cells, but after exposure to various stress signals, the protein is stabilized and activated by a series of post-translational modifications. p53 is involved in the induction of cell-cycle arrest and apoptosis through transcriptional activation of target genes. 2 p53 displays multicompartmental functions in the cell. Interestingly, in response to multiple death stimuli, mitochondrial p53 targeting occurs in a wide spectrum of cell types, where it elicits a series of responses that can promote an apoptosis through a transcription-independent mechanism. 3,4 Several lines of evidence support a connection between p53 and mitochondrion. Mitochondrial p53 levels are proportional to total p53 levels, and a small fraction of protein is associated with mitochondrial DNA (mtDNA) in the absence of exogenous stress, thus implying a non-apoptotic function for mitochondrial p53. 5 Furthermore, translocation of p53 to mitochondria was observed in various cells (e.g., MCF-7 and HCT116) independent of apoptosis. 6 p53 may be a component of a stress response pathway that involves the upregulation of mitochondrial repair in mouse liver and cancer cells, suggesting the potential role of p53 in maintaining mtDNA stability. 7,8 Mitochondrial DNA, a 16.5-kb circular double-stranded molecule, is replicated by an assembly of enzymes and proteins consisting of DNA polymerase g (pol g), ssDNAbinding protein, DNA helicase and various accessory proteins and transcription factors. 9 Mitochondrial DNA is prone to mutations, as it is localized near the inner mitochondrial membrane in which reactive oxygen species are generated. In addition, mtDNA lacks histone protection and highly efficient DNA repair...

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DNA precursor metabolism and genomic stability

Cited by 260 publications

References 123 publications

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

ITPase-deficient mice show growth retardation and die before weaning

p53 in mitochondria enhances the accuracy of DNA synthesis

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