Mcm2 is a target of regulation by Cdc7–Dbf4 during the initiation of DNA synthesis

Lei, Ming; Kawasaki, Yasuo; Young, Michael; Kihara, Makoto; Sugino, Akio; Tye, Bik Kwoon

doi:10.1101/gad.11.24.3365

Cited by 285 publications

(293 citation statements)

References 54 publications

(89 reference statements)

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“…For replication origins to become active, the pre-RC is modified at the G 1 /S transition by CDK2 and cdc7-dbf4 (Lei et al, 1997;Blow and Hodgson, 2002;Coverley et al, 2002). Interestingly, these same kinases phosphorylate the pre-RC to prevent further origin firing (Dahmann et al, 1995;Hua et al, 1997;Noton and Diffley, 2000); however, the exact mechanism(s) underlying this regulation remains unclear.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Cyclin-dependent kinase 4/6 activity is a critical determinant of pre-replication complex assembly

2008

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Cyclin-dependent kinases (CDKs) are important in regulating cell cycle transitions, particularly in coordinating DNA replication. Although the role of CDK2 activity on the replication apparatus has been extensively studied, the role of CDK4/6 in DNA replication control is less understood. Through targeted inhibition of CDK4/6 activity, we demonstrate that CDK4/6 kinase activity promotes cdc6 and cdt1 expression, and pre-replication complex (pre-RC) assembly in cycling cells. Conversely, CDK2 inhibition had no effect on the pre-RC assembly. The inhibition of pre-RC assembly is dependent on a functional retinoblastoma (RB) protein, which mediates downstream effects. As such, CDK4/6 inhibition has minimal effect on the replication apparatus in the absence of RB. The requirement of CDK4/6 was further interrogated using cells lacking D-type cyclins, in which replication complexes form normally, and correspondingly CDK4/6 inhibition had no effect on cell cycle or replication control. However, in the absence of D-type cyclins, CDK2 inhibition resulted in the attenuation of cdc6 and cdt1 levels, suggesting overlapping roles for CDK4/6 and CDK2 in regulating replication protein activity. Finally, CDK4/6 inhibition prevented the accumulation of cdc6 and cdt1 as cells progressed from mitosis through the subsequent G 1 . Combined, these studies indicate that CDK4/6 activity is important in regulating the expression of these critical mediators of DNA replication.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Cyclin-dependent kinase 4/6 activity is a critical determinant of pre-replication complex assembly

2008

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“…With the reduced level of functional MCM complex in mcm5 m850 mutants, fewer replication forks would likely be initiated, and the elongation of existing replication forks might slow, perhaps resulting in delayed progression through S phase. Interestingly, many mcm5 m850 mutant cells accumulate near 4C peak and may have finished replicating the bulk of their DNA, reminiscent of the situation in budding yeast mcm mutants, which exhibit a cell-division-cycle arrest in S phase, with a nearly doubled DNA content (41,42).…”

Section: Discussionmentioning

confidence: 99%

Depletion of minichromosome maintenance protein 5 in the zebrafish retina causes cell-cycle defect and apoptosis

Ryu

Holzschuh

Erhardt

et al. 2005

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

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In multicellular organisms, the control of genome duplication and cell division must be tightly coordinated. Essential roles of the minichromosome maintenance (MCM) proteins for genome duplication have been well established. However, no genetic model has been available to address the function of MCM proteins in the context of vertebrate organogenesis. Here, we present positional cloning of a zebrafish mcm5 mutation and characterization of its retina phenotype. In the retina, mcm5 expression correlates closely with the pattern of cell proliferation. By the third day of development, mcm5 is down-regulated in differentiated cells but is maintained in regions containing retinal stem cells. We demonstrate that a gradual depletion of maternally derived MCM5 protein leads to a prolonged S phase, cell-cycle-exit failure, apoptosis, and reduction in cell number in mcm5 m850 mutant embryos. Interestingly, by the third day of development, increased apoptosis is detectable only in the retina, tectum, and hindbrain but not in other late-proliferating tissues, suggesting that different tissues may employ distinct cellular programs in responding to the depletion of MCM5.stem cell ͉ cell proliferation ͉ ciliary marginal zone ͉ embryogenesis ͉ development P roper duplication of the genome during the cell cycle is of paramount importance for the life of an organism. In eukaryotes, each replication origin is ''licensed'' to fire once per cell cycle through the cell-cycle-dependent formation and destruction of a prereplication complex (preRC) (1-3). A key component of this preRC is a family of six structurally related proteins, MCM2 through -7, which are evolutionarily conserved in all eukaryotes. The MCM proteins were originally identified as proteins required for minichromosome maintenance in Saccharomyces cerevisiae (4). MCM2 through -7 belong to a distinct subgroup of the large AAAϩ ATPase family (5) and share a conserved central region of Ϸ200 amino acids (MCM box). Biochemical studies in Xenopus have established the role of MCM2 through -7 as replication-licensing factors (6-8). Subsequent studies illustrate that proper orchestration of the functional interactions among MCM2 through -7 proteins and other components of the preRC by cell-cycledependent protein kinases results in initiation of DNA synthesis once every cell cycle (9, 10). The MCM2 through -7 proteins appear to form heterohexamers and play important roles in initiation and elongation during DNA replication (4,11,12). Furthermore, recent evidence supports involvement of MCMs in many other chromosome transactions, including transcription, chromatin remodeling, and genome stability (13). However, in vivo analysis of MCMprotein functions in multicellular organism has been scarce. Here, we report the isolation, positional cloning, and in-depth characterization of a vertebrate mutant in an MCM-family protein. We demonstrate that the zebrafish m850 allele harbors a mutation in the mcm5 gene and exhibits developmental defects in lateproliferating tissues, including the re...

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“…(65) Mcm10 is an abundant nuclear protein with a cellular concentration comparable to that of Mcm2-Mcm7 proteins. (66,67) In S. cerevisiae, Mcm10 associates with Mcm2-Mcm7 proteins and with the nuclear chromatin. (68) A mutant MCM10 allele was defective in initiation of replication at the ARS1 origin and also induced the pausing of replication forks coming from neighboring origins.…”

Section: (A) Mcm10mentioning

confidence: 99%

Perpetuating the double helix: molecular machines at eukaryotic DNA replication origins

2003

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SummaryThe hardest part of replicating a genome is the beginning. The first step of DNA replication (called ''initiation'') mobilizes a large number of specialized proteins (''initiators'') that recognize specific sequences or structural motifs in the DNA, unwind the double helix, protect the exposed ssDNA, and recruit the enzymatic activities required for DNA synthesis, such as helicases, primases and polymerases. All of these components are orderly assembled before the first nucleotide can be incorporated. On the occasion of the 50th anniversary of the discovery of the DNA structure, we review our current knowledge of the molecular mechanisms that control initiation of DNA replication in eukaryotic cells, with particular emphasis on the recent identification of novel initiator proteins. We speculate how these initiators assemble molecular machines capable of performing specific biochemical tasks, such as loading a ringshaped helicase onto the DNA double helix.

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Mcm2 is a target of regulation by Cdc7–Dbf4 during the initiation of DNA synthesis

Cited by 285 publications

References 54 publications

RETRACTED ARTICLE: Cyclin-dependent kinase 4/6 activity is a critical determinant of pre-replication complex assembly

RETRACTED ARTICLE: Cyclin-dependent kinase 4/6 activity is a critical determinant of pre-replication complex assembly

Depletion of minichromosome maintenance protein 5 in the zebrafish retina causes cell-cycle defect and apoptosis

Perpetuating the double helix: molecular machines at eukaryotic DNA replication origins

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