Dual functions of CDC6: a yeast protein required for DNA replication also inhibits nuclear division.

Bueno, Avelino; Russell, Paul

doi:10.1002/j.1460-2075.1992.tb05276.x

Cited by 133 publications

(114 citation statements)

References 47 publications

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“…Wild-type Cdc6 will also reload onto chromatin during G2/M (Tanaka et al, 1997) and cause rereplication in an ORC2* ORC6* strain (Figures 5 and 6) if, but only if, it is overexpressed. We believe this is because Cdc6 is a CDK inhibitor (Bueno and Russell, 1992;Calzada et al, 2001). When overexpressed, it inhibits CDK, and so may allow the accumulation of some unphosphorylated Cdc6.…”

Section: Discussionmentioning

confidence: 95%

“…CDK activity regulates transcription, degradation, and nuclear localization of Cdc6 (Bueno and Russell, 1992;Zwerschke et al, 1994; Results were assayed after 3 d on galactose plates at 30°C. In most cases, four independent transformants were tested; colony growth was scored as follows: ϩ, normal growth; s, small and visible to the eye (typically more than 1000 cells); m, micro-colony (typically Ͻ1000 cells); d, dead and no visible growth.…”

Section: Discussionmentioning

confidence: 99%

“…First, the fact that multiple mechanisms of regulation are interleaved and dependent on CDK activity. Second, Cdc6 is itself a CDK inhibitor (Bueno and Russell, 1992;Elsasser et al, 1996;Calzada et al, 2001), so any manipulation that results in relatively high Cdc6 abundance has the ability to inhibit CDK activity and feedback on multiple mechanisms of regulation ( Figure 1). These difficulties are exemplified in the studies of Tanaka et al (1997), who found that ectopically expressed Cdc6 could reload onto chromatin in G2/M.…”

Section: Introductionmentioning

confidence: 99%

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Roles of the CDK Phosphorylation Sites of Yeast Cdc6 in Chromatin Binding and Rereplication

Honey

Futcher

2007

MBoC

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The Saccharomyces cerevisiae Cdc6 protein is crucial for DNA replication. In the absence of cyclin-dependent kinase (CDK) activity, Cdc6 binds to replication origins, and loads Mcm proteins. In the presence of CDK activity, Cdc6 does not bind to origins, and this helps prevent rereplication. CDK activity affects Cdc6 function by multiple mechanisms: CDK activity affects transcription of CDC6, degradation of Cdc6, nuclear import of Cdc6, and binding of Cdc6 to Clb2. Here we examine some of these mechanisms individually. We find that when Cdc6 is forced into the nucleus during late G1 or S, it will not substantially reload onto chromatin no matter whether its CDK sites are present or not. In contrast, at a G2/M nocodazole arrest, Cdc6 will reload onto chromatin if and only if its CDK sites have been removed. Trace amounts of nonphosphorylatable Cdc6 are dominant lethal in strains bearing nonphosphorylatable Orc2 and Orc6, apparently because of rereplication. This synthetic dominant lethality occurs even in strains with wild-type MCM genes. Nonphosphorylatable Cdc6, or Orc2 and Orc6, sensitize cells to rereplication caused by overexpression of various replication initiation proteins such as Dpb11 and Sld2.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Roles of the CDK Phosphorylation Sites of Yeast Cdc6 in Chromatin Binding and Rereplication

Honey

Futcher

2007

MBoC

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“…In an analogous way, perhaps the tight association of Cdc18 with the Cdc2 kinase accounts for the cell cycle arrest when Cdc18 is overexpressed, either by Cdc2 or by preventing association of Cdc2 with other relevant targets. In this regard, it is interesting that S. cerevisiae CDC6 appeared as a high-copy suppressor of an S. pombe mutant strain that undergoes lethal mitosis due to premature activation of Cdc2 kinase (Bueno and Russell, 1992). High expression of CDC6 delays the onset of mitosis in both S. pombe and S. cerevisiae wild-type strains.…”

Section: Discussionmentioning

confidence: 99%

Negative Regulation of Cdc18 DNA Replication Protein by Cdc2

López-Girona

Mondésert

Leatherwood

et al. 1998

MBoC

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Fission yeast Cdc18, a homologue of Cdc6 in budding yeast and metazoans, is periodically expressed during the S phase and required for activation of replication origins. Cdc18 overexpression induces DNA rereplication without mitosis, as does elimination of Cdc2-Cdc13 kinase during G2 phase. These findings suggest that illegitimate activation of origins may be prevented through inhibition of Cdc18 by Cdc2. Consistent with this hypothesis, we report that Cdc18 interacts with Cdc2 in association with Cdc13 and Cig2 B-type cyclins in vivo. Cdc18 is phosphorylated by the associated Cdc2 in vitro. Mutation of a single phosphorylation site, T104A, activates Cdc18 in the rereplication assay. The cdc18-K9 mutation is suppressed by a cig2 mutation, providing genetic evidence that Cdc2-Cig2 kinase inhibits Cdc18. Moreover, constitutive expression of Cig2 prevents rereplication in cells lacking Cdc13. These findings identify Cdc18 as a key target of Cdc2-Cdc13 and Cdc2-Cig2 kinases in the mechanism that limits chromosomal DNA replication to once per cell cycle.

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“…CDC6, CDC46, and CDC47 are all transcribed at about the same time as SWI4 (Bueno and Russell 1992;Zwerschke et al 1994;Dalton and Whitbread 1995). These proteins are required for the initiation of DNA synthesis (for review, see Stillman 1996), and defects in these genes cause a high rate of minichromosome loss that can be suppressed by increasing the number of replication origins on the DNA (Brewer and Fangman 1987;Hogan and Koshland 1992).…”

mentioning

confidence: 99%

A novel Mcm1-dependent element in the SWI4, CLN3, CDC6, and CDC47 promoters activates M/G1-specific transcription.

McInerny¹,

Partridge²,

Mikesell³

et al. 1997

Genes Dev.

200

183

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We have identified a novel promoter element that confers M/Gl-specific transcription in Saccharomyces cerevisiae. This element, which we call an ECB (early cell cycle box), was first identified in the SWI4 promoter, but it is also present in the promoter of a G 1 cyclin CLN3, as well as in the promoters of three DNA replication genes: CDC6, CDC47, and CDC46. Transcripts from all five of these genes oscillate during the cell cycle and peak at the M/G1 boundary, as do isolated ECB elements in reporter constructs. The ECB element contains an Mcml binding site to which Mcml binds in vitro, and an Mcml-VP16 fusion, which places a constitutive activator on Mcml-binding sites in vivo, can deregulate ECB-containing promoters. Mcml is a transcription factor that is also required for minichromosome maintenance. We provide evidence that the replication defect of mcml mutants can be suppressed by ectopic CDC6 transcription. Periodic expression of SWI4 and CLN3 may be important for cell cycle progression, as we find that these genes are both haploinsufficient and rate limiting for G1 progression. We suggest that ECB-regulated gene products play critical roles in promoting the initiation of S-phase, both by regulating CLN1 and CLN2 transcription and as components of the initiation complex on origins of replication.

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Dual functions of CDC6: a yeast protein required for DNA replication also inhibits nuclear division.

Cited by 133 publications

References 47 publications

Roles of the CDK Phosphorylation Sites of Yeast Cdc6 in Chromatin Binding and Rereplication

Roles of the CDK Phosphorylation Sites of Yeast Cdc6 in Chromatin Binding and Rereplication

Negative Regulation of Cdc18 DNA Replication Protein by Cdc2

A novel Mcm1-dependent element in the SWI4, CLN3, CDC6, and CDC47 promoters activates M/G1-specific transcription.

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