Hierarchy of S-Phase-Promoting Factors: Yeast Dbf4-Cdc7 Kinase Requires Prior S-Phase Cyclin-Dependent Kinase Activation

Nougarede, R.; Seta, Flavio Della; Zarzov, Patrick; Schwob, Étienne

doi:10.1128/mcb.20.11.3795-3806.2000

Cited by 121 publications

(110 citation statements)

References 80 publications

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“…Therefore, phosphorylation of Mcm2 by CDK generates at least two additional phosphorylation sites ( 26 S and 40 S) for Cdc7 kinase. Previous in vivo studies in S. cerevisiae also suggested that the sequential action of CDK and Cdc7 kinase is essential for the initiation of DNA replication (25). During S phase, Cdc7 kinase supports DNA replication only after CDK activation.…”

Section: S Pombementioning

confidence: 96%

CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein

Cho

Lee

Kong

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

114

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Cdc7 is an essential kinase required for the initiation of eukaryotic DNA replication. Previous studies in many species showed that the minichromosome maintenance complex is a major physiological target of this kinase. In this study, we have mapped the sites in human Mcm2 protein that are phosphorylated by Cdc7. The in vitro phosphorylation of several Mcm2 truncated proteins and peptides revealed that Mcm2 contains two major ( 5 S and 53 S) and at least three minor phosphorylation sites ( 4 S, 7 S, and 59 T) located at the N-terminal region. Alanine substitution experiments with Mcm2 peptides showed that the phosphorylation of 5 S and 53 S by Cdc7 required the presence of an acidic amino acid adjacent to a serine residue. Furthermore, although Cdc7 was unable to phosphorylate a Mcm2 peptide (spanning amino acids 19 -30 and containing 26 S and 27 S), it phosphorylated 26 S efficiently when this peptide contained a chemically synthesized phospho-27 S modification. Hence, additional Cdc7 phosphorylation sites could be generated in Mcm2 by its prior phosphorylation by a cyclin-dependent kinase. This finding may explain why the sequential action of cyclindependent and Cdc7 kinases is essential for the initiation of DNA replication.replication ͉ prereplicative complex ͉ origin activation C dc7 plays an essential role in the initiation of eukaryotic DNA replication (1-3). Cdc7 encodes a serine͞threonine kinase that is highly conserved from yeast to human (4). The activity of this kinase fluctuates during the cell cycle and depends completely on the regulatory subunit, Dbf4. Dbf4 accumulates during the S and G 2 phases of the cell cycle and is degraded rapidly during the G 1 phase by the anaphase promoting complex (5, 6). In Saccharomyces cerevisiae, Dbf4 binds to chromatin at the G 1 ͞S transition and remains on chromatin during the S phase (7). In the Xenopus egg extract cell-free system, Cdc7 was found to bind to chromatin during S phase, and this association required the minichromosome maintenance (MCM) complex (8).Both genetic and biochemical studies in S. cerevisiae indicate that Cdc7 kinase activity is required throughout S phase to activate replication origins on chromosomes (9). Cdc7 kinase acts directly on individual replication origins, presumably by phosphorylating components of the prereplicative complex (pre-RC), which may lead to the remodeling of the pre-RC for the unwinding of replication origins and subsequent recruitment of the replication fork machinery. Although the mechanism-oforigin activation by Cdc7 kinase remains unclear, the MCM complex appears to be the primary physiological target of this kinase activity (2).The MCM complex is composed of six distinct subunits (Mcm2, Mcm3, Mcm4, Mcm5, Mcm6, and Mcm7), which are all related structurally and highly conserved in eukaryotes (10). All six proteins are essential for the initiation of DNA replication and contain sequence motifs required for DNA helicase activity. In keeping with this notion, the MCM subcomplex containing Mcm4, Mcm6, and Mcm7 posses...

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Section: S Pombementioning

confidence: 96%

CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein

Cho

Lee

Kong

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

114

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“…immediately prior to replication origin firing). However, under these conditions, cells are budded, indicating that G 1 -S cyclins have been activated (36) and furthermore present S phase-specific cyclin-dependent kinase activity (37).…”

Section: Initiation Of Dna Replication Is Necessary For Manifestationmentioning

confidence: 99%

Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair

Bart

Angers

Fortier

et al. 2016

Journal of Biological Chemistry

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Nucleotide excision repair (NER) is a highly conserved pathway that removes helix-distorting DNA lesions induced by a plethora of mutagens, including UV light. Our laboratory previously demonstrated that human cells deficient in either ATM and Rad3-related (ATR) kinase or translesion DNA polymerase (i.e. key proteins that promote the completion of DNA replication in response to UV-induced replicative stress) are characterized by profound inhibition of NER exclusively during S phase. Toward elucidating the mechanistic basis of this phenomenon, we developed a novel assay to quantify NER kinetics as a function of cell cycle in the model organism Saccharomyces cerevisiae. Using this assay, we demonstrate that in yeast, deficiency of the ATR homologue Mec1 or of any among several other proteins involved in the cellular response to replicative stress significantly abrogates NER uniquely during S phase. Moreover, initiation of DNA replication is required for manifestation of this defect, and S phase NER proficiency is correlated with the capacity of individual mutants to respond to replicative stress. Importantly, we demonstrate that partial depletion of Rfa1 recapitulates defective S phase-specific NER in wild type yeast; moreover, ectopic RPA1-3 overexpression rescues such deficiency in either ATR-or polymerase -deficient human cells. Our results strongly suggest that reduction of NER capacity during periods of enhanced replicative stress, ostensibly caused by inordinate sequestration of RPA at stalled DNA replication forks, represents a conserved feature of the multifaceted eukaryotic DNA damage response.

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“…The preRC renders chromosomes competent for initiation of DNA replication, but initiation does not occur because cells have not yet committed to S phase. Both cyclin-dependent protein kinases (CDKs; Cdc28p-Clb5p and -Clb6p) and Cdc7p-Dbf4p are required for S phase commitment by activating origin firing and promoting loading of Cdc45p (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

Section: T He Initiation Of Dna Replication In Saccharomyces Cerevisiaementioning

confidence: 99%

Binding of cyclin-dependent kinases to ORC and Cdc6p regulates the chromosome replication cycle

Weinreich

Liang

Chen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Cdc6p and the origin recognition complex (ORC) are essential for assembly of a pre-replicative complex (preRC) at origins of replication, before the initiation of DNA synthesis. In the absence of Cdc6p, cells fail to initiate DNA replication and undergo a ''reductional'' mitosis, in which the unreplicated chromosomes are randomly segregated to the spindle poles. We show here that the cells harboring a mutation in the essential Cdc6p Walker A-box arrest in late mitosis, probably at anaphase. This cell cycle block requires either the three Cdc28p phosphorylation sites within the N terminus of Cdc6p or a short region (aa 8 -17) that contains a Cy (Cyclin) interaction sequence. These same two Cdc6p mutants that allow a reductional mitosis are defective in binding Cdc28p kinase. In addition to Cdc6p, ORC also binds to cyclin-dependent kinases (CDKs). Interestingly, Sic1p, a CDK inhibitor protein, blocked the S phase-specific Cdc28p-Clb5p kinase from interacting with ORC, but did not prevent the G1-specific Cdc28p-Cln2p kinase-ORC interaction. We suggest that ORC, Cdc6p, and Sic1p bind to different CDKs in a cell cycle-dependent manner to temporally regulate events that (i) allow preRC formation after mitosis, (ii) prevent mitosis before DNA replication can occur, and (iii) promote initiation of DNA replication.

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Hierarchy of S-Phase-Promoting Factors: Yeast Dbf4-Cdc7 Kinase Requires Prior S-Phase Cyclin-Dependent Kinase Activation

Cited by 121 publications

References 80 publications

CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein

CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein

Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair

Binding of cyclin-dependent kinases to ORC and Cdc6p regulates the chromosome replication cycle

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