Involvement of deoxycytidylate deaminase in the response to Sn1-type methylation DNA damage in budding yeast

Liskay, R. Michael; Wheeler, Linda J.; Mathews, Christopher K.; Erdeniz, Naz

doi:10.1016/j.cub.2007.07.028

Cited by 3 publications

(4 citation statements)

References 16 publications

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“…Significantly, this process does not appear to require checkpoint proteins. We failed to identify the deoxycytidine deaminase dcd1 mutant, recently reported to confer MNNG resistance to a rad52 mgt1 strain, which was of similar magnitude to that seen with the rad52 mgt1 msh2 or rad52 mgt1 mlh1 strains (Liskay et al 2007). Examination of the library revealed that this deletion strain was missing from our collection.…”

Section: Resultsmentioning

confidence: 71%

“…In our search for factors mediating MNNG sensitivity, we identified solely the known MMR factors Msh2, Msh6, Mlh1, and Pms1. The four MMR proteins, together with Dcd1 identified in the Liskay laboratory (Liskay et al 2007), thus appear to be the only nonredundant and nonessential factors required for MNNG-induced killing in S. cerevisiae. Incidentally, the fact that we did not find any DNA damage signaling mutants showed that checkpoint pathways do not mediate the toxicity of methylating agents in yeast.…”

Section: Discussionmentioning

confidence: 95%

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Interplay of DNA Repair Pathways Controls Methylation Damage Toxicity in Saccharomyces cerevisiae

Ćejka

Jiricny

2008

Genetics

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Section: Resultsmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 95%

Interplay of DNA Repair Pathways Controls Methylation Damage Toxicity in Saccharomyces cerevisiae

Ćejka

Jiricny

2008

Genetics

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“…Investigations of dCMP deaminase in a genetically tractable organism have been carried out with the budding yeast Saccharomyces cerevisiae (29,38). As predicted, null mutations of the DCD1 dCMP deaminase gene significantly increase dCTP and decrease dTTP pools, resulting in an ϳ125-fold increase in the dCTP/dTTP ratio.…”

mentioning

confidence: 93%

Replication Fork Collapse and Genome Instability in a Deoxycytidylate Deaminase Mutant

Sánchez

Sharma

Rozenzhak

et al. 2012

Molecular and Cellular Biology

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dRibonucleotide reductase (RNR) and deoxycytidylate deaminase (dCMP deaminase) are pivotal allosteric enzymes required to maintain adequate pools of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis and repair. Whereas RNR inhibition slows DNA replication and activates checkpoint responses, the effect of dCMP deaminase deficiency is largely unknown. Here, we report that deleting the Schizosaccharomyces pombe dcd1 ؉ dCMP deaminase gene (SPBC2G2.13c) increases dCTP ϳ30-fold and decreases dTTP ϳ4-fold. In contrast to the robust growth of a Saccharomyces cerevisiae dcd1⌬ mutant, fission yeast dcd1⌬ cells delay cell cycle progression in early S phase and are sensitive to multiple DNA-damaging agents, indicating impaired DNA replication and repair. DNA content profiling of dcd1⌬ cells differs from an RNR-deficient mutant. Dcd1 deficiency activates genome integrity checkpoints enforced by Rad3 (ATR), Cds1 (Chk2), and Chk1 and creates critical requirements for proteins involved in recovery from replication fork collapse, including the ␥H2AX-binding protein Brc1 and Mus81 Holliday junction resolvase. These effects correlate with increased nuclear foci of the single-stranded DNA binding protein RPA and the homologous recombination repair protein Rad52. Moreover, Brc1 suppresses spontaneous mutagenesis in dcd1⌬ cells. We propose that replication forks stall and collapse in dcd1⌬ cells, burdening DNA damage and checkpoint responses to maintain genome integrity.T he accurate duplication of a eukaryotic genome demands abundant supplies of deoxyribonucleoside triphosphates (dNTPs), which are the building blocks of DNA. Much of the burden for providing both ample and balanced pools of dNTPs falls to two allosteric enzymes: ribonucleotide reductase (RNR) and deoxycytidylate deaminase (dCMP deaminase) (22,31,40). RNR plays essential roles in the de novo biosynthesis of all four dNTPs required for DNA synthesis, while dCMP deaminase is specifically involved in the production of dTTP (Fig. 1). Whereas the physiological consequences of RNR defects have been investigated in great detail (9,15,47), the effects of dCMP deaminase deficiency are much less well understood, despite its presumptive key roles in efficient genome duplication and in influencing the outcomes of nucleoside-based antitumor and antiviral therapies (24,25,34).Investigations of dCMP deaminase in a genetically tractable organism have been carried out with the budding yeast Saccharomyces cerevisiae (29, 38). As predicted, null mutations of the DCD1 dCMP deaminase gene significantly increase dCTP and decrease dTTP pools, resulting in an ϳ125-fold increase in the dCTP/dTTP ratio. Surprisingly, these dNTP pool imbalances do not reduce growth rates or have other obvious effects but rather modestly increase mutagenesis rates (29). In contrast, chemical or mutational inhibition of RNR slows DNA replication and activates checkpoint responses. Thus, RNR and dCMP deaminase deficiencies have quite different effects in Saccharomyces cerevisiae.The fission yeast Schizos...

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“…Intriguingly, we do observe a reduction of up to 2-fold in the levels of dCTP relative to total NTP levels. Although it is possible that this reduction in dCTP could impinge on replication rate, we note that similar reductions of dTTP in budding yeast have no impact on S-phase progression (Kohalmi et al, 1991; Liskay et al, 2007). …”

Section: Discussionmentioning

confidence: 74%

Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase

Liew¹,

Lim

Cohen

et al. 2016

Cell Reports

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SUMMARYIn many organisms, hydroxyurea (HU) inhibits class I ribonucleotide reductase, leading to lowered cellular pools of deoxyribonucleoside triphosphates. The reduced levels for DNA precursors is believed to cause replication fork stalling. Upon treatment of the hyperthermophilic archaeon Sulfolobus solfataricus with HU, we observe dose-dependent cell cycle arrest, accumulation of DNA double-strand breaks, stalled replication forks, and elevated levels of recombination structures. However, Sulfolobus has a HU-insensitive class II ribonucleotide reductase, and we reveal that HU treatment does not significantly impact cellular DNA precursor pools. Profiling of protein and transcript levels reveals modulation of a specific subset of replication initiation and cell division genes. Notably, the selective loss of the regulatory subunit of the primase correlates with cessation of replication initiation and stalling of replication forks. Furthermore, we find evidence for a detoxification response induced by HU treatment.

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Involvement of deoxycytidylate deaminase in the response to Sn1-type methylation DNA damage in budding yeast

Cited by 3 publications

References 16 publications

Interplay of DNA Repair Pathways Controls Methylation Damage Toxicity in Saccharomyces cerevisiae

Interplay of DNA Repair Pathways Controls Methylation Damage Toxicity in Saccharomyces cerevisiae

Replication Fork Collapse and Genome Instability in a Deoxycytidylate Deaminase Mutant

Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase

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