Ccr4 contributes to tolerance of replication stress through control of<i>CRT1</i>mRNA poly(A) tail length

Woolstencroft, Robert N.; Cook, Michael A.; Preiß, Thomas; Durocher, Daniel; Tyers, Mike

doi:10.1242/jcs.03221

Cited by 59 publications

(73 citation statements)

References 74 publications

(111 reference statements)

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“…In addition, recent evidence has implicated Ccr4 in the DNA replication checkpoint where it regulates the mRNA poly(A) tail length of the Crt1 transcriptional repressor (Westmoreland et al 2004;Woolstencroft et al 2006). Furthermore, CCR4 has been identified as a gene required for the G 1 -phase cell cycle transition in irradiated cells (Westmoreland et al 2004;Woolstencroft et al 2006). Finally, Ccr4 To examine genetic interactions, diploid cells with the indicated gene deletions were created and mid-log-phase YPD-grown cells were sized.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, many Ccr4-Not complex components associate or interact genetically with gene products with known cell cycle roles (e.g., Clb2, Cdc73, Dbf2, Paf1, and Sic1) (Liu et al 1997;Chang et al 1999;Gavin et al 2002;Pan et al 2006). Also, recent evidence has implicated Ccr4 and Caf1 in the DNA replication checkpoint (Woolstencroft et al 2006). Moreover, Ccr4-Not complex components appear to be essential for G 1 -phase cell cycle transition in irradiated cells (Westmoreland et al 2004).…”

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confidence: 99%

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Ccr4 Alters Cell Size in Yeast by Modulating the Timing of CLN1 and CLN2 Expression

Manukyan

Zhang²,

Thippeswamy

et al. 2008

Genetics

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Large, multisubunit Ccr4-Not complexes are evolutionarily conserved global regulators of gene expression. Deletion of CCR4 or several components of Ccr4-Not complexes results in abnormally large cells. Since yeast must attain a critical cell size at Start to commit to division, the large size of ccr4D cells implies that they may have a size-specific proliferation defect. Overexpression of CLN1, CLN2, CLN3, and SWI4 reduces the size of ccr4D cells, suggesting that ccr4D cells have a G 1 -phase cyclin deficiency. In support of this, we find that CLN1 and CLN2 expression and budding are delayed in ccr4D cells. Moreover, overexpression of CCR4 advances the timing of CLN1 expression, promotes premature budding, and reduces cell size. Genetic analyses suggest that Ccr4 functions independently of Cln3 and downstream of Bck2. Thus, like cln3Dbck2D double deletions, cln3Dccr4D cells are also inviable. However, deletion of Whi5, a transcriptional repressor of CLN1 and CLN2, restores viability. We find that Ccr4 negatively regulates the half-life of WHI5 mRNAs, and we conclude that, by modulating the stability of WHI5 mRNAs, Ccr4 influences the size-dependent timing of G 1 -phase cyclin transcription.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Ccr4 Alters Cell Size in Yeast by Modulating the Timing of CLN1 and CLN2 Expression

Manukyan

Zhang²,

Thippeswamy

et al. 2008

Genetics

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“…Ribonucleotide reductase (RNR) activity, which converts ribonu-cleotides into deoxyribonucleotides, is upregulated during replication stress. Full induction of RNR activity requires Dun1, and in a parallel pathway, Pop2 and Ccr4 (components of the Ccr4-Not complex) (Huang et al 1998;Zhao and Rothstein 2002;Mulder et al 2005;Woolstencroft et al 2006). In addition, there are several links between glycine metabolism and de novo purine biosynthesis (Subramanian et al 2005;Christensen and Mackenzie 2006).…”

Section: Loh On Chromosome IIImentioning

confidence: 99%

A Genetic Screen for Increased Loss of Heterozygosity inSaccharomyces cerevisiae

et al. 2008

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Loss of heterozygosity (LOH) can be a driving force in the evolution of mitotic/somatic diploid cells, and cellular changes that increase the rate of LOH have been proposed to facilitate this process. In the yeast Saccharomyces cerevisiae, spontaneous LOH occurs by a number of mechanisms including chromosome loss and reciprocal and nonreciprocal recombination. We performed a screen in diploid yeast to identify mutants with increased rates of LOH using the collection of homozygous deletion alleles of nonessential genes. Increased LOH was quantified at three loci (MET15, SAM2, and MAT ) on three different chromosomes, and the LOH events were analyzed as to whether they were reciprocal or nonreciprocal in nature. Nonreciprocal LOH was further characterized as chromosome loss or truncation, a local mutational event (gene conversion or point mutation), or break-induced replication (BIR). The 61 mutants identified could be divided into several groups, including ones that had locusspecific effects. Mutations in genes involved in DNA replication and chromatin assembly led to LOH predominantly via reciprocal recombination. In contrast, nonreciprocal LOH events with increased chromosome loss largely resulted from mutations in genes implicated in kinetochore function, sister chromatid cohesion, or relatively late steps of DNA recombination. Mutants of genes normally involved in early steps of DNA damage repair and signaling produced nonreciprocal LOH without an increased proportion of chromosome loss. Altogether, this study defines a genetic landscape for the basis of increased LOH and the processes by which it occurs.

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“…Prior studies have implicated both the 9-1-1 complex and the CCR4-NOT complex as key regulators of ribonucleotide reductase, and mutants in these pathways exhibit depleted nucleotide pools and are sensitive to replication stress (Zhao et al 2001;Westmoreland et al 2004;Mulder et al 2005;Traven et al 2005;Woolstencroft et al 2006). Moreover, a ccr4-D tel1-D strain has been previously shown to exhibit enhanced sensitivity to the ribonucleotide reductase inhibitor hydroxyurea (Woolstencroft et al 2006).…”

Section: Gcrs In Tel1-d Xxx-d Strainsmentioning

confidence: 99%

Novel Connections Between DNA Replication, Telomere Homeostasis, and the DNA Damage Response Revealed by a Genome-Wide Screen for TEL1/ATM Interactions in Saccharomyces cerevisiae

2013

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Tel1 is the budding yeast ortholog of the mammalian tumor suppressor and DNA damage response (DDR) kinase ATM. However, tel1-D cells, unlike ATM-deficient cells, do not exhibit sensitivity to DNA-damaging agents, but do display shortened (but stably maintained) telomere lengths. Neither the extent to which Tel1p functions in the DDR nor the mechanism by which Tel1 contributes to telomere metabolism is well understood. To address the first question, we present the results from a comprehensive genome-wide screen for genetic interactions with tel1-D that cause sensitivity to methyl methanesulfonate (MMS) and/or ionizing radiation, along with follow-up characterizations of the 13 interactions yielded by this screen. Surprisingly, many of the tel1-D interactions that confer DNA damage sensitivity also exacerbate the short telomere phenotype, suggesting a connection between these two phenomena. Restoration of normal telomere length in the tel1-D xxx-D mutants results in only minor suppression of the DNA damage sensitivity, demonstrating that the sensitivity of these mutants must also involve mechanisms independent of telomere length.In support of a model for increased replication stress in the tel1-D xxx-D mutants, we show that depletion of dNTP pools through pretreatment with hydroxyurea renders tel1-D cells (but not wild type) MMS-sensitive, demonstrating that, under certain conditions, Tel1p does indeed play a critical role in the DDR.

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Ccr4 contributes to tolerance of replication stress through control ofCRT1mRNA poly(A) tail length

Cited by 59 publications

References 74 publications

Ccr4 Alters Cell Size in Yeast by Modulating the Timing of CLN1 and CLN2 Expression

Ccr4 Alters Cell Size in Yeast by Modulating the Timing of CLN1 and CLN2 Expression

A Genetic Screen for Increased Loss of Heterozygosity inSaccharomyces cerevisiae

Novel Connections Between DNA Replication, Telomere Homeostasis, and the DNA Damage Response Revealed by a Genome-Wide Screen for TEL1/ATM Interactions in Saccharomyces cerevisiae

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