Regulation of chromosome dynamics by Hsk1/Cdc7 kinase

Matsumoto, Seiji; Masai, Hisao

doi:10.1042/bst20130217

Cited by 17 publications

(16 citation statements)

References 73 publications

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“…In particular, CDC7 is known to be involved in DNA repair. 43 It is possible that a temporal phosphorylation of Cac1p by CDC7 could contribute to the response to DNA damage, but this effect is tied to other CDC7 regulated events. The only detectable consequence of the mutations in the kinase target sites was a reduction in telomeric gene silencing (Fig.…”

Section: Discussionmentioning

confidence: 99%

CDC28 phosphorylates Cac1p and regulates the association of chromatin assembly factor i with chromatin

et al. 2015

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Chromatin Assembly Factor I (CAF-I) plays a key role in the replication-coupled assembly of nucleosomes. It is expected that its function is linked to the regulation of the cell cycle, but little detail is available. Current models suggest that CAF-I is recruited to replication forks and to chromatin via an interaction between its Cac1p subunit and the replication sliding clamp, PCNA, and that this interaction is stimulated by the kinase CDC7. Here we show that another kinase, CDC28, phosphorylates Cac1p on serines 94 and 515 in early S phase and regulates its association with chromatin, but not its association with PCNA. Mutations in the Cac1p-phosphorylation sites of CDC28 but not of CDC7 substantially reduce the in vivo phosphorylation of Cac1p. However, mutations in the putative CDC7 target sites on Cac1p reduce its stability. The association of CAF-I with chromatin is impaired in a cdc28-1 mutant and to a lesser extent in a cdc7-1 mutant. In addition, mutations in the Cac1p-phosphorylation sites by both CDC28 and CDC7 reduce gene silencing at the telomeres. We propose that this phosphorylation represents a regulatory step in the recruitment of CAF-I to chromatin in early S phase that is distinct from the association of CAF-I with PCNA. Hence, we implicate CDC28 in the regulation of chromatin reassembly during DNA replication. These findings provide novel mechanistic insights on the links between cell-cycle regulation, DNA replication and chromatin reassembly.

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Section: Discussionmentioning

confidence: 99%

CDC28 phosphorylates Cac1p and regulates the association of chromatin assembly factor i with chromatin

et al. 2015

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“…Dbf4-dependent kinase (DDK) comprises the kinase Cdc7 and regulatory subunit Dbf4 (Matsumoto and Masai, 2013). DDK functions throughout meiosis and promotes ZMM-mediated crossing over through phosphorylation of Zip1 (Chen et al, 2015).…”

Section: Msh4 Phosphorylation Is Catalyzed By Dbf4-dependent Kinase mentioning

confidence: 99%

The crossover function of MutSγ is activated via Cdc7-dependent stabilization of Msh4

Rao

Tang

et al. 2018

Preprint

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The MutSγ complex, Msh4-Msh5, binds DNA joint-molecule (JM) intermediates during homologous recombination to promote crossing over and accurate chromosome segregation at the first division of meiosis. MutSγ facilitates the formation and biased resolution of crossoverspecific JM intermediates called double Holliday junctions. Here we show that these activities are governed by regulated proteasomal degradation. MutSγ is initially inactive for crossing over due to an N-terminal degron on Msh4 that renders it unstable. Activation of MutSγ requires the Dbf4-dependent kinase, Cdc7 (DDK), which directly phosphorylates and thereby neutralizes the Msh4 degron. Phosphorylated Msh4 is chromatin bound and requires DNA strand exchange and chromosome synapsis, implying that DDK specifically targets MutSγ that has already bound nascent JMs. Our study establishes regulated protein degradation as a fundamental mechanism underlying meiotic crossover control. the differentiation of crossover sites manifests as the selective retention and accumulation of specific recombination factors. One such factor is MutSγ, a heterodimer of Msh4 and Msh5, two homologs of the DNA mismatch-recognition factor MutS (Manhart and Alani, 2016;Snowden et al., 2004). Msh4 and Msh5 are members the ZMM proteins (Zip1, Zip2, Zip3, Zip4, Msh4, Msh5, Mer3, and Spo16), a diverse set of activities that facilitate crossover-specific events of recombination, and couple these events to chromosome synapsis (Fung et al., 2004;Hunter, 2015;Lynn et al., 2007;Shinohara et al., 2008). As seen in a variety of species, initial numbers of MutSγ immunostaining foci greatly outnumber final crossover numbers (De Muyt et al., 2014; de Vries et al., 1999;Edelmann et al., 1999;Higgins et al., 2008;Kneitz et al., 2000;Yokoo et al., 2012;Zhang et al., 2014). As prophase I progresses, MutSγ is lost from most recombination sites but retained at sites that will go on to mature into crossovers. This patterning process is dependent on the Zip3/RNF212/ZHP-3/HEI10 family of RING E3 ligases (Agarwal and Roeder, Wang et al., 2012;Yokoo et al., 2012;Zhang et al., 2018). Additional evidence implicates the SUMO-modification and ubiquitin-proteasome systems in meiotic crossover control (Ahuja et al., 2017; Rao et al., 2017) and suggests a model in which factors such as MutSγ are selectively stabilized at crossover sites by protecting them from proteolysis. Implicit in this model is the notion that MutSγ may be intrinsically unstable.Here, we show that regulated proteolysis plays a direct and essential role in meiotic crossing over. Msh4 is identified as an intrinsically unstable protein that is targeted for proteasomal degradation by an N-terminal degron thereby rendering MutSγ inactive for crossing over. Activation of MutSγ occurs by neutralizing the Msh4 degron via Cdc7-catalyzed phosphorylation. Thus, a key meiotic pro-crossover factor is activated by attenuating its proteolysis.

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“…DDK ( D bf4- D ependent K inase or Cdc7-Dbf4 kinase) is a conserved Ser/Thr protein kinase that regulates the initiation of DNA replication, meiotic recombination, mutagenesis, and chromatid cohesion (for recent reviews, see (Araki 2016, Matsumoto and Masai 2013, Rossbach and Sclafani 2016). The role of DDK is conserved in evolution as expression of human DDK can substitute for yeast DDK in yeast cells (Davey, et al 2011).…”

Section: Introduction: Ddk and Dna Replicationmentioning

confidence: 99%

O Cdc7 kinase where art thou?

Sclafani

Hesselberth

2017

Curr Genet

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Although Cdc7 protein kinase is important for regulating DNA replication in all eukaryotes and is a target for cancer therapy, it has never been localized in cells. Recently, a novel molecular genomic method was used by our laboratory to localize Cdc7 to regions of chromosomes. Originally, mutations in the CDC7 gene were found in the classic cdc mutant collection of Lee Hartwell (Hartwell, et al. 1973). The CDC7 gene was found to encode a protein kinase called DDK that has been studied for many years, establishing its precise role in the initiation of DNA replication at origins. Recently, clinical studies are underway with DDK inhibitors against DDK in cancer patients. However, the conundrum is that Cdc7 has never been detected at origins of replication even though many studies have suggested it should be there. We used “Calling Card” system in which DNA binding proteins are localized to the genome via retrotransposon insertion and deep-sequencing methods. We have shown that Cdc7 localizes at many regions of the genome and was enriched at functional origins of replication. These results are consistent with DDK’s role in many additional genomic processes including mutagenesis, chromatid cohesion, and meiotic recombination. Thus, the main conclusion from our studies is that Cdc7 kinase is found at many locations in the genome, but is enriched at functional origins of replication. Furthermore, we propose that application of the Calling Card system to other eukaryotes should be useful in identification of functional origins in other eukaryotic cells.

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Regulation of chromosome dynamics by Hsk1/Cdc7 kinase

Cited by 17 publications

References 73 publications

CDC28 phosphorylates Cac1p and regulates the association of chromatin assembly factor i with chromatin

CDC28 phosphorylates Cac1p and regulates the association of chromatin assembly factor i with chromatin

The crossover function of MutSγ is activated via Cdc7-dependent stabilization of Msh4

O Cdc7 kinase where art thou?

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