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Coupling histone homeostasis to centromere integrity via the ubiquitin-proteasome system.

Takayama Y, Toda T - Cell Div (2010)

Bottom Line: We have found that Ams2 stability varies during the cell cycle, and that the ubiquitin-proteasome pathway is responsible for Ams2 instability.Our results indicate that excess synthesis of core histones outside S phase results in deleterious effects on cell survival.Finally, we address the significance and potential implications of our work from an evolutionary point of view.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cell Biology, Institute of Life Science, Kurume University, 1-1 Hyakunen-kohen, Kurume, Fukuoka 839-0864, Japan. yutakaya@lsi.kurume-u.ac.jp.

ABSTRACT
In many eukaryotes, histone gene expression is regulated in a cell cycle-dependent manner, with a spike pattern at S phase. In fission yeast the GATA-type transcription factor Ams2 is required for transcriptional activation of all the core histone genes during S phase and Ams2 protein levels per se show concomitant periodic patterns. We have recently unveiled the molecular mechanisms underlying Ams2 fluctuation during the cell cycle. We have found that Ams2 stability varies during the cell cycle, and that the ubiquitin-proteasome pathway is responsible for Ams2 instability. Intriguingly, Ams2 proteolysis requires Hsk1-a Cdc7 homologue in fission yeast generally called Dbf4-dependent protein kinase (DDK)-and the SCF ubiquitin ligase containing the substrate receptor Pof3 F-box protein. Here, we discuss why histone synthesis has to occur only during S phase. Our results indicate that excess synthesis of core histones outside S phase results in deleterious effects on cell survival. In particular, functions of the centromere, in which the centromere-specific H3 variant CENP-A usually form centromeric nucleosomes, are greatly compromised. This defect is, at least in part, ascribable to abnormal incorporation of canonical histone H3 into these nucleosomes. Finally, we address the significance and potential implications of our work from an evolutionary point of view.

No MeSH data available.


Related in: MedlinePlus

Cooperative roles of CDK and DDK in cell cycle progression from G1 to G2 phase. CDK and DDK promote G1-S phase transition and are required for proper S phase progression (arrows). In addition, these two kinases act in concert during G2 phase. CDK is required for prevention of chromosomal DNA re-replication, whereas DDK is essential to repress untimely histone gene expression, thereby helping ensure centromere integrity.
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Figure 5: Cooperative roles of CDK and DDK in cell cycle progression from G1 to G2 phase. CDK and DDK promote G1-S phase transition and are required for proper S phase progression (arrows). In addition, these two kinases act in concert during G2 phase. CDK is required for prevention of chromosomal DNA re-replication, whereas DDK is essential to repress untimely histone gene expression, thereby helping ensure centromere integrity.

Mentions: Our work illuminates interesting, unexpected parallels between CDK and DDK during the cell cycle, in particular their roles during G2 phase. It is well established that CDK is important to prevent re-replication of chromosomes upon completion of S phase [40]. In contrast, it is generally believed that DDK's major, if not sole, role lies in S phase, although previous work in yeast indicated that this might not always be true [41,42]. Our study clearly showed that DDK is needed to degrade Ams2 during G2 phase, thereby preventing unnecessary histone gene expression during the post-S phase period. Hence, CDK and DDK not only share roles in S phase initiation and progression, but are also required to secure proper passage of G2 phase upon completion of S phase. CDK is required for restraining deleterious re-replication of the genome, whereas DDK prevents extra histone transcription, which would result in global and local genome disturbance, including centromere malfunction (Figure 5).


Coupling histone homeostasis to centromere integrity via the ubiquitin-proteasome system.

Takayama Y, Toda T - Cell Div (2010)

Cooperative roles of CDK and DDK in cell cycle progression from G1 to G2 phase. CDK and DDK promote G1-S phase transition and are required for proper S phase progression (arrows). In addition, these two kinases act in concert during G2 phase. CDK is required for prevention of chromosomal DNA re-replication, whereas DDK is essential to repress untimely histone gene expression, thereby helping ensure centromere integrity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2910015&req=5

Figure 5: Cooperative roles of CDK and DDK in cell cycle progression from G1 to G2 phase. CDK and DDK promote G1-S phase transition and are required for proper S phase progression (arrows). In addition, these two kinases act in concert during G2 phase. CDK is required for prevention of chromosomal DNA re-replication, whereas DDK is essential to repress untimely histone gene expression, thereby helping ensure centromere integrity.
Mentions: Our work illuminates interesting, unexpected parallels between CDK and DDK during the cell cycle, in particular their roles during G2 phase. It is well established that CDK is important to prevent re-replication of chromosomes upon completion of S phase [40]. In contrast, it is generally believed that DDK's major, if not sole, role lies in S phase, although previous work in yeast indicated that this might not always be true [41,42]. Our study clearly showed that DDK is needed to degrade Ams2 during G2 phase, thereby preventing unnecessary histone gene expression during the post-S phase period. Hence, CDK and DDK not only share roles in S phase initiation and progression, but are also required to secure proper passage of G2 phase upon completion of S phase. CDK is required for restraining deleterious re-replication of the genome, whereas DDK prevents extra histone transcription, which would result in global and local genome disturbance, including centromere malfunction (Figure 5).

Bottom Line: We have found that Ams2 stability varies during the cell cycle, and that the ubiquitin-proteasome pathway is responsible for Ams2 instability.Our results indicate that excess synthesis of core histones outside S phase results in deleterious effects on cell survival.Finally, we address the significance and potential implications of our work from an evolutionary point of view.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cell Biology, Institute of Life Science, Kurume University, 1-1 Hyakunen-kohen, Kurume, Fukuoka 839-0864, Japan. yutakaya@lsi.kurume-u.ac.jp.

ABSTRACT
In many eukaryotes, histone gene expression is regulated in a cell cycle-dependent manner, with a spike pattern at S phase. In fission yeast the GATA-type transcription factor Ams2 is required for transcriptional activation of all the core histone genes during S phase and Ams2 protein levels per se show concomitant periodic patterns. We have recently unveiled the molecular mechanisms underlying Ams2 fluctuation during the cell cycle. We have found that Ams2 stability varies during the cell cycle, and that the ubiquitin-proteasome pathway is responsible for Ams2 instability. Intriguingly, Ams2 proteolysis requires Hsk1-a Cdc7 homologue in fission yeast generally called Dbf4-dependent protein kinase (DDK)-and the SCF ubiquitin ligase containing the substrate receptor Pof3 F-box protein. Here, we discuss why histone synthesis has to occur only during S phase. Our results indicate that excess synthesis of core histones outside S phase results in deleterious effects on cell survival. In particular, functions of the centromere, in which the centromere-specific H3 variant CENP-A usually form centromeric nucleosomes, are greatly compromised. This defect is, at least in part, ascribable to abnormal incorporation of canonical histone H3 into these nucleosomes. Finally, we address the significance and potential implications of our work from an evolutionary point of view.

No MeSH data available.


Related in: MedlinePlus