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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.

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General view of the species-specific regulation of histone homeostasis. In mammals (left) [45], histone transcription is activated by NPAT (Nuclear protein, ataxia-telangiectasia locus) and SLBP is then bound to the 3' end of histone mRNA, by which it prevents degradation of mRNAs, resulting in synthesis of histone proteins. At the end of S phase, CDK1-cyclinA (cycA) phosphorylates SLBP to trigger its degradation, restraining further transcription of histone mRNAs. In fission yeast (middle) [20], Ams2 activates histone transcription at G1/S phase. At the S/G2 phase, Ams2 is phosphorylated by DDK, leading to degradation via the SCFPof3-ubiquitin proteasome pathway. In budding yeast (left) [36], excess histones are recognised and phosphorylated by Rad53. The histone-Rad53 complex is recognised by the Ubc4/5 (E2) and Tom1 (E3) and is polyubiquitylated. Histones with a polyubiquitin chain are degraded by the proteasome.
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Figure 4: General view of the species-specific regulation of histone homeostasis. In mammals (left) [45], histone transcription is activated by NPAT (Nuclear protein, ataxia-telangiectasia locus) and SLBP is then bound to the 3' end of histone mRNA, by which it prevents degradation of mRNAs, resulting in synthesis of histone proteins. At the end of S phase, CDK1-cyclinA (cycA) phosphorylates SLBP to trigger its degradation, restraining further transcription of histone mRNAs. In fission yeast (middle) [20], Ams2 activates histone transcription at G1/S phase. At the S/G2 phase, Ams2 is phosphorylated by DDK, leading to degradation via the SCFPof3-ubiquitin proteasome pathway. In budding yeast (left) [36], excess histones are recognised and phosphorylated by Rad53. The histone-Rad53 complex is recognised by the Ubc4/5 (E2) and Tom1 (E3) and is polyubiquitylated. Histones with a polyubiquitin chain are degraded by the proteasome.

Mentions: In budding yeast, histone levels, in particular those of non-chromatin forms, are regulated by phosphorylation and the ubiquitin-proteasome pathway [36]. In this regulatory system, excess free histones are phosphorylated by Rad53 (homologues of fission yeast Cds1 and human CHK1/2), resulting in polyubiquitylation via the Ubc4/Ubc5 (E2) and Tom1 (E3) and subsequent degradation by the proteasome (Figure 4, right). Although not shown in fission yeast, it is noteworthy that in budding yeast and fly, CENP-A protein levels are strictly regulated by the ubiquitin-proteasome system [37,38]. Therefore, at least in yeast, the histone levels are under the control of phosphorylation and the ubiquitin-proteasome system.


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

Takayama Y, Toda T - Cell Div (2010)

General view of the species-specific regulation of histone homeostasis. In mammals (left) [45], histone transcription is activated by NPAT (Nuclear protein, ataxia-telangiectasia locus) and SLBP is then bound to the 3' end of histone mRNA, by which it prevents degradation of mRNAs, resulting in synthesis of histone proteins. At the end of S phase, CDK1-cyclinA (cycA) phosphorylates SLBP to trigger its degradation, restraining further transcription of histone mRNAs. In fission yeast (middle) [20], Ams2 activates histone transcription at G1/S phase. At the S/G2 phase, Ams2 is phosphorylated by DDK, leading to degradation via the SCFPof3-ubiquitin proteasome pathway. In budding yeast (left) [36], excess histones are recognised and phosphorylated by Rad53. The histone-Rad53 complex is recognised by the Ubc4/5 (E2) and Tom1 (E3) and is polyubiquitylated. Histones with a polyubiquitin chain are degraded by the proteasome.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: General view of the species-specific regulation of histone homeostasis. In mammals (left) [45], histone transcription is activated by NPAT (Nuclear protein, ataxia-telangiectasia locus) and SLBP is then bound to the 3' end of histone mRNA, by which it prevents degradation of mRNAs, resulting in synthesis of histone proteins. At the end of S phase, CDK1-cyclinA (cycA) phosphorylates SLBP to trigger its degradation, restraining further transcription of histone mRNAs. In fission yeast (middle) [20], Ams2 activates histone transcription at G1/S phase. At the S/G2 phase, Ams2 is phosphorylated by DDK, leading to degradation via the SCFPof3-ubiquitin proteasome pathway. In budding yeast (left) [36], excess histones are recognised and phosphorylated by Rad53. The histone-Rad53 complex is recognised by the Ubc4/5 (E2) and Tom1 (E3) and is polyubiquitylated. Histones with a polyubiquitin chain are degraded by the proteasome.
Mentions: In budding yeast, histone levels, in particular those of non-chromatin forms, are regulated by phosphorylation and the ubiquitin-proteasome pathway [36]. In this regulatory system, excess free histones are phosphorylated by Rad53 (homologues of fission yeast Cds1 and human CHK1/2), resulting in polyubiquitylation via the Ubc4/Ubc5 (E2) and Tom1 (E3) and subsequent degradation by the proteasome (Figure 4, right). Although not shown in fission yeast, it is noteworthy that in budding yeast and fly, CENP-A protein levels are strictly regulated by the ubiquitin-proteasome system [37,38]. Therefore, at least in yeast, the histone levels are under the control of phosphorylation and the ubiquitin-proteasome system.

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