Hydroxyurea

Timson, J.

doi:10.1016/0165-1110(75)90002-0

Cited by 238 publications

(113 citation statements)

References 76 publications

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“…A deletion event, produced by "slippage" of the nascent strand on its template, gives rise to lacZ reversion. diphosphates to deoxynucleotide diphosphates, thereby depleting precursor pools for DNA synthesis (Timson 1975). We used sublethal doses of HU during expansion of the cultures and measured Lac 1 reversion rates in the deletion and QP5 reporters, as well as a transition mutation (AT to GC) and a frameshift (11G) reporter.…”

Section: Resultsmentioning

confidence: 99%

Insights Into Mutagenesis Using Escherichia coli Chromosomal lacZ Strains That Enable Detection of a Wide Spectrum of Mutational Events

et al. 2011

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Strand misalignments at DNA repeats during replication are implicated in mutational hotspots. To study these events, we have generated strains carrying mutations in the Escherichia coli chromosomal lacZ gene that revert via deletion of a short duplicated sequence or by template switching within imperfect inverted repeat (quasipalindrome, QP) sequences. Using these strains, we demonstrate that mutation of the distal repeat of a quasipalindrome, with respect to replication fork movement, is about 10-fold higher than the proximal repeat, consistent with more common template switching on the leading strand. The leading strand bias was lost in the absence of exonucleases I and VII, suggesting that it results from more efficient suppression of template switching by 39 exonucleases targeted to the lagging strand. The loss of 39 exonucleases has no effect on strand misalignment at direct repeats to produce deletion. To compare these events to other mutations, we have reengineered reporters (designed by Cupples and Miller 1989) that detect specific base substitutions or frameshifts in lacZ with the reverting lacZ locus on the chromosome rather than an F9 element. This set allows rapid screening of potential mutagens, environmental conditions, or genetic loci for effects on a broad set of mutational events. We found that hydroxyurea (HU), which depletes dNTP pools, slightly elevated templated mutations at inverted repeats but had no effect on deletions, simple frameshifts, or base substitutions. Mutations in nucleotide diphosphate kinase, ndk, significantly elevated simple mutations but had little effect on the templated class. Zebularine, a cytosine analog, elevated all classes.

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Section: Resultsmentioning

confidence: 99%

Insights Into Mutagenesis Using Escherichia coli Chromosomal lacZ Strains That Enable Detection of a Wide Spectrum of Mutational Events

et al. 2011

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“…It is difficult to calculate the exact amount of hydroxyurea administered but the ingested quantity was probably in the range of 0.3-3 mg/g, based on the average worker body weight and estimated food consumption. Hydroxyurea has a general cytostatic effect well below these concentrations (Timson, 1975) and the resistance of the honeybee intestinal stem cells therefore seems remarkable. The significant, repeatable treatment effect on survival provides independent confirmation that the dose used was biologically active.…”

Section: Discussionmentioning

confidence: 99%

Age, caste, and behavior determine the replicative activity of intestinal stem cells in honeybees (Apis mellifera L.)

Ward

Coleman

Clinnin

et al. 2008

Experimental Gerontology

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Abstract:Honeybees (Apis mellifera L.) display a pronounced natural aging plasticity. The differences in aging rates between the alternative phenotypes and behavioral classes could reflect differences in protection against damage or in the ability to repair vulnerable tissues. As in other animals, including humans, the gut is continually exposed to environmental insults and harbors a large population of replicating stem cells that maintain the intestinal epithelium. Through studies of the major internal organs using incorporation and immunodetection of the mitotic marker bromodeoxyuridine, the intestine was determined to be the main site of tissue renewal in adult honeybees. Proliferative activity of the intestinal stem cells was compared among queens, workers, and males of different ages. Simultaneous attempts to assess intestinal cell loss via apoptosis yielded inconclusive results. The relationship between intestinal cell proliferation and worker life-history was evaluated in greater depth by studying diutinus winter workers, reproductive workers, and by decoupling worker behavioral status from chronological age in a single-cohort colony. Intestinal cell proliferation was abundant in all groups and showed an agerelated decline in workers, queens, and males. At young ages, workers exhibited relatively more intestinal cell proliferation than did queens and queens more than drones, but the caste and sex differences decreased with age. Cell proliferation did not decrease beyond 6 weeks of age in older queens and in diutinus workers. Ovary activation did not correlate with the amount of intestinal stem cell proliferation in workers, although the queenless hive condition was associated with lower overall counts. In the single-cohort colony, nurse bees exhibited more cell proliferation than foragers, regardless of age. The overall results do not support our hypothesis that longer-lived phenotypes exhibit increased somatic repair in the form of higher replicative activity of intestinal stem cells. Instead, the observed proliferation patterns reflect differential demands for digestive activity in the different groups, which result in different requirements for replacement of lost intestinal cells. The maintenance of proliferative capacity for over 1 year suggests that queen intestinal stem cells have a relatively high replicative potential, but further studies are needed to relate honeybee lifespan differences to cellular aging.

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“…Thus, asynchronously growing HeLa1 cells can be an appropriate source for isolating unduplicated centrosomes. It has been shown that when exposed to DNA synthesis, inhibitors such as hydroxyurea (HU; an inhibitor of ribonucleotide reductase (Timson, 1975)), majority of the unduplicated centrosomes complete duplication, yet further duplication (re-duplication) of duplicated centrosomes is suppressed in the presence of p53 (Tarapore and Fukasawa, 2002). Because HeLa1 cells contain functional p53, most unduplicated centrosomes complete duplication, but further duplication is suppressed during HU-induced arrest.…”

Section: Characterization Of Centrosomal Localization Of Mortalinmentioning

confidence: 99%

Mortalin controls centrosome duplication via modulating centrosomal localization of p53

Izumi

Kanai

et al. 2006

Oncogene

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Abnormal amplification of centrosomes, commonly found in human cancer, is the major cause of mitotic defects and chromosome instability in cancer cells. Like DNA, centrosomes duplicate once in each cell cycle, hence the defect in the mechanism that ensures centrosome duplication to occur once and only once in each cell cycle results in abnormal amplification of centrosomes and mitotic defects. Centrosomes are non-membranous organelles, and undergo dynamic changes in its constituents during the centrosome duplication cycle. Through a comparative mass spectrometric analysis of unduplicated and duplicated centrosomes, we identified mortalin, a member of heat shock protein family, as a protein that associates preferentially with duplicated centrosomes. Further analysis revealed that mortalin localized to centrosomes in late G1 before centrosome duplication, remained at centrosomes during S and G2, and dissociated from centrosomes during mitosis. Overexpression of mortalin overrides the p53-dependent suppression of centrosome duplication, and mortalin-driven centrosome duplication requires physical interaction between mortalin and p53. Moreover, mortalin promotes dissociation of p53 from centrosomes through physical interaction. The p53 mutant that lacks the ability to bind to mortalin remains at centrosomes, and suppresses centrosome duplication in a transactivation function-independent manner. Thus, our present findings not only identify mortalin as an upstream molecule of p53 but also provide evidence for the involvement of centrosomally localized p53 in the regulation of centrosome duplication.

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Hydroxyurea

Cited by 238 publications

References 76 publications

Insights Into Mutagenesis Using Escherichia coli Chromosomal lacZ Strains That Enable Detection of a Wide Spectrum of Mutational Events

Insights Into Mutagenesis Using Escherichia coli Chromosomal lacZ Strains That Enable Detection of a Wide Spectrum of Mutational Events

Age, caste, and behavior determine the replicative activity of intestinal stem cells in honeybees (Apis mellifera L.)

Mortalin controls centrosome duplication via modulating centrosomal localization of p53

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