Cell cycle- and differentiation stage-dependent variation of dUTPase activity in higher plant cells

Pardo, Emilia G.; Gutiérrez, Crisanto

doi:10.1016/0014-4827(90)90214-u

Cited by 33 publications

(28 citation statements)

References 31 publications

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“…As cells progress through S and into G2 plus M phase, the level of de novo synthesis decreases substantially. Interestingly, a similar pattern of dUTPase activity has been reported in higher plants (28). Undifferentiated resting root meristem cells have high dUTPase levels independent of cell proliferation, whereas dUTPase levels in proliferating root meristem cells increase in a cell cycle-dependent manner.…”

Section: Discussionsupporting

confidence: 75%

Maturation stage and proliferation-dependent expression of dUTPase in human T cells.

Strahler

Zhu

Hora

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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We have developed a database of lymphoid polypeptides detected by two-dimensional polyacrylamide gel electrophoresis to aid in studies of leukemogenesis and of mutation affecting protein structure. In prior studies, we observed a 19-kDa phosphopolypeptide which was induced with proliferation in mature T cells and constitutively expressed in immature thymocytes. In this report we describe the identififcation of this polypeptide as the phosphorylated form of dUTPase (EC 3.6.1.23), following cDNA cloning of the gene, based on a partial amino acid sequence of the phosphopolypeptide. Studies of the expression and phosphorylation of dUTPase in human T cells indicate that accumulation and phosphorylation of dUTPase in mature T cells occur in a cell cycle-dependent manner. Interestingly, noncycling immature thymocytes express constitutively high levels of phosphorylated and unphosphorylated dUTPase. These results suggest an important role for dUTPase in immature thymocytes that is independent of proliferation.

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Section: Discussionsupporting

confidence: 75%

Maturation stage and proliferation-dependent expression of dUTPase in human T cells.

Strahler

Zhu

Hora

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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“…The inhibition of dUTPase activity leading to an increased level of G-to-A transitions appears to have a phenotype similar to that of vpr null mutant HIV-1 or vpr null mutant HIV-1 trans complemented with Vpr*W54R in the mutation rate assay. Both primate and nonprimate lentiviruses have the ability to replicate in nondividing cells, which are presumed to have low levels of S-phase cellular enzymes involved in DNA synthesis and repair, such as dUTPase and UNG (19,29,37). The encoding of dUTPase by nonprimate lentiviruses and the incorporation of UNG by primate lentiviruses such as HIV-1 by its interaction with Vpr support the hypothesis that these different mechanisms evolved in order for these viruses to remove uracil from their DNA when replicating in nondividing cells.…”

Section: Discussionmentioning

confidence: 99%

The Interaction of Vpr with Uracil DNA Glycosylase Modulates the Human Immunodeficiency Virus Type 1 In Vivo Mutation Rate

Mansky

Prévéral

Selig

et al. 2000

J Virol

163

188

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The Vpr protein of human immunodeficiency virus type 1 (HIV-1) influences the in vivo mutation rate of the virus. Since Vpr interacts with a cellular protein implicated in the DNA repair process, uracil DNA glycosylase (UNG), we have explored the contribution of this interaction to the mutation rate of HIV-1. Single-amino-acid variants of Vpr were characterized for their differential UNG-binding properties and used to trans complement vpr null mutant HIV-1. A striking correlation was established between the abilities of Vpr to interact with UNG and to influence the HIV-1 mutation rate. We demonstrate that Vpr incorporation into virus particles is required to influence the in vivo mutation rate and to mediate virion packaging of the nuclear form of UNG. The recruitment of UNG into virions indicates a mechanism for how Vpr can influence reverse transcription accuracy. Our data suggest that distinct mechanisms evolved in primate and nonprimate lentiviruses to reconcile uracil misincorporation into lentiviral DNA.

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“…Studies of dUTPase in plants suggest that expression is linked to the rate of proliferation, as demonstrated by a close association of dUTPase activity and replicative vegetative and floral meristem regions (16,17). Recently, the dUTPase gene was isolated from the human fungal pathogen, Candida albicans, the expression of which is governed in part by an MluI cell cycle box element located in the promoter region (18).…”

mentioning

confidence: 99%

The Human dUTPase Gene Encodes both Nuclear and Mitochondrial Isoforms

Ladner

Caradonna

1997

Journal of Biological Chemistry

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We have previously identified distinct nuclear and mitochondrial isoforms of dUTPase in human cells, reporting the cDNA sequence of the nuclear isoform (DUT-N). We now report a cDNA corresponding to the mitochondrial isoform (DUT- dUTPase (EC 3.6.1.23) catalyzes the hydrolysis of dUTP to dUMP and pyrophosphate, simultaneously removing dUTP from the DNA biosynthetic pathway and providing substrate (dUMP) for the de novo synthesis of thymidylate (1). The importance of the dUTPase function in prokaryotic, eukaryotic, and viral systems has been firmly established in recent years. dUTPase is essential for viability in Escherichia coli and Saccharomyces cerevisiae and was shown to be required for efficient DNA replication in several viral systems (2-5). The importance of the dUTPase function in the human system has been further distinguished by its importance in anti-thymidylate chemotherapy.MThymidylate metabolism has been an important target for the development of widely utilized chemotherapeutic agents such as 5-fluorouracil, fluorodeoxyuridine, and ZD1694 that are used in the treatment of breast and gastrointestinal tumors. The enzymatic target of these compounds, thymidylate synthase (TS), 1 generates dTMP from dUMP and a folate cofactor. Investigations by several laboratories suggest that the basis of cytotoxicity caused by inhibition of de novo thymidylate metabolism may be the accumulation of excessive dUTP pools (6 -9). TS inhibition induces a dramatic elevation of dUTP pools resulting in chronic dUMP misincorporation into DNA during replication and repair, leading to DNA fragmentation and cell death (7). Work published by Curtin et al. (7) demonstrates a significant correlation between intracellular dUTP levels and the magnitude of DNA damage resulting from TS inhibition. dUTPase (the major regulator of dUTP pools in humans) plays a protective role by limiting dUTP accumulation in the cell and countering the cytotoxic effect of TS inhibition. Recently, direct evidence supporting this role was demonstrated. Overexpression of the E. coli dUTPase in HT29 human colorectal tumor cells resulted in the induction of resistance to the TS inhibitor fluorodeoxyuridine (10). These studies provide substantial evidence suggesting that levels of the dUTPase enzyme may be a critical factor in determining fluorodeoxyuridine toxicity in certain cancer types. The essential nature of dUTPase during

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Cell cycle- and differentiation stage-dependent variation of dUTPase activity in higher plant cells

Cited by 33 publications

References 31 publications

Maturation stage and proliferation-dependent expression of dUTPase in human T cells.

Maturation stage and proliferation-dependent expression of dUTPase in human T cells.

The Interaction of Vpr with Uracil DNA Glycosylase Modulates the Human Immunodeficiency Virus Type 1 In Vivo Mutation Rate

The Human dUTPase Gene Encodes both Nuclear and Mitochondrial Isoforms

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