Dbf4-Dependent Cdc7 Kinase Links DNA Replication to the Segregation of Homologous Chromosomes in Meiosis I

Matos, Joao; Lipp, Jesse J.; Bogdanova, Aliona; Guillot, Sylvine; Okaz, Elwy; Junqueira, Magno; Shevchenko, Andrej; Zachariae, Wolfgang

doi:10.1016/j.cell.2008.10.026

Cited by 162 publications

(268 citation statements)

References 42 publications

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“…For instance, Cdc5 might be required for full activation of Cdc7 during meiosis. Consistent with this idea, Cdc5 physically interacts with Cdc7 during meiosis I [58].…”

Section: Iii) Protection Of Centromeric Cohesionsupporting

confidence: 73%

How to halve ploidy: lessons from budding yeast meiosis

Kerr¹,

Sarkar²,

Arumugam³

2012

Cell. Mol. Life Sci.

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“…For instance, Cdc5 might be required for full activation of Cdc7 during meiosis. Consistent with this idea, Cdc5 physically interacts with Cdc7 during meiosis I [58].…”

Section: Iii) Protection Of Centromeric Cohesionsupporting

confidence: 73%

How to halve ploidy: lessons from budding yeast meiosis

Kerr¹,

Sarkar²,

Arumugam³

2012

Cell. Mol. Life Sci.

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“…These results clearly show that Cac1p is not phosphorylated in G1 and that under permissive conditions the cdc7-1 and cdc28-1 alleles do not preclude its phosphorylation in S phase. Importantly, at 37 C there was an approximate 2-fold decrease in the phosphorylation of Cac1p in cdc28-1 as compared to wild type and cdc7-1 cells (Fig. 1D, lanes 4, 8, 12).…”

Section: Cdk Is the Main Cac1p-kinase In Vivomentioning

confidence: 99%

“…Conversely, the lack of effect in cdc7-1 cells could be due to slow progression through S phase, 17 which could be past the point of Cac1p phosphorylation by DDK. To address these issues, we synchronized W303, cdc7-1 and cdc28-1 cells in G1 with a-factor for 3 hours, released them toward S phase and then shifted half of the cultures to 37 C for 30 min. This treatment is expected to inactivate DDK and CDK in S phase.…”

Section: Cdk Is the Main Cac1p-kinase In Vivomentioning

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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“…The timing of Dbf4 destruction suggests that Dbf4 has postreplicative functions. Indeed, recent work has shown that Dbf4 prevents premature exit from mitosis and also controls the segregation of homologous chromosomes in meiosis I by a direct interaction with Cdc5, the only Polo-like kinase in budding yeast (Matos et al 2008;. Rad53-mediated phosphorylation of Dbf4 postpones late-origin firing during replication stress (Lopez-Mosqueda et al 2010;Duch et al 2011) but Cdc7-Dbf4 kinase activity is reduced only twofold by Rad53-dependent Dbf4 phosphorylation (Weinreich and Stillman 1999).…”

mentioning

confidence: 99%

DNA Replication Checkpoint Signaling Depends on a Rad53–Dbf4 N-Terminal Interaction in Saccharomyces cerevisiae

et al. 2013

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Dbf4-dependent kinase (DDK) and cyclin-dependent kinase (CDK) are essential to initiate DNA replication at individual origins. During replication stress, the S-phase checkpoint inhibits the DDK-and CDK-dependent activation of late replication origins. Rad53 kinase is a central effector of the replication checkpoint and both binds to and phosphorylates Dbf4 to prevent late-origin firing. The molecular basis for the Rad53-Dbf4 physical interaction is not clear but occurs through the Dbf4 N terminus. Here we found that both Rad53 FHA1 and FHA2 domains, which specifically recognize phospho-threonine (pT), interacted with Dbf4 through an N-terminal sequence and an adjacent BRCT domain. Purified Rad53 FHA1 domain (but not FHA2) bound to a pT Dbf4 peptide in vitro, suggesting a possible phospho-threonine-dependent interaction between FHA1 and Dbf4. The Dbf4-Rad53 interaction is governed by multiple contacts that are separable from the Cdc5-and Msa1-binding sites in the Dbf4 N terminus. Importantly, abrogation of the Rad53-Dbf4 physical interaction blocked Dbf4 phosphorylation and allowed late-origin firing during replication checkpoint activation. This indicated that Rad53 must stably bind to Dbf4 to regulate its activity.T HE fidelity of chromosome replication depends on checkpoint mechanisms to stabilize stalled forks, regulate origin activation, and repair DNA damage (Hartwell and Weinert 1989;Bartek et al. 2004;Segurado and Tercero 2009). In response to replication stress, the replication checkpoint maintains replisome stability and prevents late origins from firing, which allows time for DNA repair and the completion of DNA replication prior to chromosome segregation. Incomplete DNA replication or uncoordinated origin firing following DNA damage can result in genomic instability, cancer predisposition, and premature aging (Branzei and Foiani 2010).In the budding yeast Saccharomyces cerevisiae, activation of the checkpoint sensor kinase Mec1 (vertebrate ATR, Ataxia Telangiectasia and Rad3-related) is triggered at stalled forks or sites of DNA damage (Majka et al. 2006;Labib and De Piccoli 2011). Subsequent signal amplification through the Mrc1 or Rad9 adaptors leads to activation of the checkpoint kinase Rad53 (the ortholog of the human tumor suppressor Chk2) (Branzei and Foiani 2009). Rad53 is an integral transducer of various cellular responses to replication stress or DNA damage. Rad53 induces a series of transcriptional responses through MBF-regulated genes (Bastos de Oliveira et al. 2012;Travesa et al. 2012) and also activates the Dun1 kinase, which promotes the expression of ribonucleotide reductase (RNR) subunits and additional DNA repair genes (Huang et al. 1998). In parallel, Rad53 down-regulates the RNR inhibitor Sml1 to increase deoxyribonucleotide levels and facilitate DNA synthesis (Zhao et al. 2001). In response to replication fork stalling, Rad53 prevents the activation of late replication origins by phosphorylating two proteins required for the initiation of DNA replication: Dbf4 and Sld3 (...

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Dbf4-Dependent Cdc7 Kinase Links DNA Replication to the Segregation of Homologous Chromosomes in Meiosis I

Cited by 162 publications

References 42 publications

How to halve ploidy: lessons from budding yeast meiosis

How to halve ploidy: lessons from budding yeast meiosis

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

DNA Replication Checkpoint Signaling Depends on a Rad53–Dbf4 N-Terminal Interaction in Saccharomyces cerevisiae

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