Regulation of Initiation of S Phase, Replication Checkpoint Signaling, and Maintenance of Mitotic Chromosome Structures during S Phase by Hsk1 Kinase in the Fission Yeast

Takeda, Tomomi; Ogino, Keiko; Tatebayashi, Kazuo; Ikeda, Hideo; Arai, Kohei; Masai, Hisao

doi:10.1091/mbc.12.5.1257

Cited by 108 publications

(136 citation statements)

References 78 publications

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“…We previously reported hsk1-89, a temperature-sensitive allele of hsk1 ϩ encoding the fission yeast Cdc7 homologue, and showed that hsk1 ϩ function is essential for mitotic S phase (14). We noticed that the hsk1-89͞ hsk1-89 homozygous diploid cells frequently failed to complete meiosis, and most cells were arrested with one nucleus (Fig.…”

Section: Resultsmentioning

confidence: 84%

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Hsk1 kinase is required for induction of meiotic dsDNA breaks without involving checkpoint kinases in fission yeast

Ogino¹,

Hirota

Matsumoto³

et al. 2006

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

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Cdc7 kinase, conserved through evolution, is known to be essential for mitotic DNA replication. The role of Cdc7 in meiotic recombination was suggested in Saccharomyces cerevisiae, but its precise role has not been addressed. Here, we report that Hsk1, the Cdc7-related kinase in Schizosaccharomyces pombe, plays a crucial role during meiosis. In a hsk1 temperature-sensitive strain (hsk1-89), meiosis is arrested with one nucleus state before meiosis I in most of the cells and meiotic recombination frequency is reduced by one order of magnitude, whereas premeiotic DNA replication is delayed but is apparently completed. Strikingly, formation of meiotic dsDNA breaks (DSBs) are largely impaired in the mutant, and Hsk1 kinase activity is essential for these processes. Deletion of all three checkpoint kinases, namely Cds1, Chk1, and Mek1, does not restore DSB formation, meiosis, or Cdc2 activation, which is suppressed in hsk1-89, suggesting that these aberrations are not caused by known checkpoint pathways but that Hsk1 may regulate DSB formation and meiosis. Whereas transcriptional induction of some rec genes and horsetail movement are normal, chromatin remodeling at ade6-M26, a recombination hotspot, which is prerequisite for subsequent DSB formation at this locus, is not observed in hsk1-89. These results indicate unique and essential roles of Hsk1 kinase in the initiation of meiotic recombination and meiosis.Cdc7-related kinase ͉ checkpoint control ͉ chromatin remodeling ͉ meiosis ͉ meiotic recombination A lthough recent studies revealed the presence of a number of conserved factors involved in mitotic DNA replication (1), it is largely unknown whether they play roles in meiotic replication and recombination (2, 3). Studies in fission and budding yeasts indicated essential roles of Cdc2 kinase (1) and Clb5-and Clb6-dependent Cdc28 kinase (4), respectively, in premeiotic DNA replication. Orc, Cdc18, and MCM are also required for premeiotic DNA synthesis (3, 5), although their requirement may not be identical to that during mitotic replication (2). It is not known whether initiation is regulated by a common mechanism or the same set of replication origins is used during premeiotic S phase. In budding yeast, strong coupling of DNA replication and meiotic recombination has been shown (6-9).Cdc7 kinase plays an essential role in firing replication origins during mitotic growth (10, 11). It was reported previously that meiotic recombination frequency is reduced, whereas premeiotic DNA replication proceeds, in the budding yeast cdc7 ts mutants and that Cdc7 may play a role in synaptonemal complex formation during meiosis, a step stabilizing homologous pairing during meiotic recombination (12,13), but the precise meiotic roles of Cdc7 have remained elusive. We report here that Hsk1, the fission yeast homologue of Cdc7 kinase, is required for efficient meiotic recombination and meiotic nuclear division. During meiosis, Hsk1 is required specifically for formation of dsDNA breaks (DSBs), an early event for meiotic recombinatio...

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Section: Resultsmentioning

confidence: 84%

“…We previously reported that sister chromatid cohesion during mitosis is partially impaired in hsk1-89 cells (14). It is an intriguing possibility that defective meiotic sister chromatid cohesion in hsk1-89 may lead to impaired chromatin remodeling, a prerequisite for meiotic recombination.…”

Section: Discussionmentioning

confidence: 97%

Hsk1 kinase is required for induction of meiotic dsDNA breaks without involving checkpoint kinases in fission yeast

Ogino¹,

Hirota

Matsumoto³

et al. 2006

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

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“…The accumulation of XDbf4 during maturation could indicate that the XCdc7/Dbf4 complex is required for meiosis. Alternatively, the potential involvement of XCdc7/Dbf4 in sister chromatid cohesion, origin recognition complex localization, or gene regulation, as shown in different organisms, could explain why the complex binds to chromatin in a pre-RC independent manner (12,40,42,43). Additional studies will be needed to define the role of XCdc7/Dbf4 during the early embryonic cell cycle and determine whether a zygotic version of the XCdc7/Drf1 complex is also required for initiation of DNA replication during the somatic cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Xenopus CDC7/DRF1 Complex Is Required for the Initiation of DNA Replication

Silva

Bradley

Gao

et al. 2006

Journal of Biological Chemistry

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The Cdc7 kinase is essential for the initiation of DNA replication in eukaryotes. Two regulatory subunits of the Xenopus Cdc7 kinase have been identified: XDbf4 and XDrf1. In this study we determined the expression pattern of XDbf4 and XDrf1 and examined their involvement in DNA replication. We show that XDrf1 expression is restricted to oogenesis and early embryos, whereas XDbf4 is expressed throughout development. Immunodepletion from Xenopus egg extracts indicated that both proteins are only found in complexes with XCdc7 and there is a 5-fold molar excess of the XCdc7/Drf1 over SCdc7/Dbf4 complexes. Both complexes exhibit kinase activity and are differentially phosphorylated during the cell cycle. Depletion of the XCdc7/Drf1 from egg extracts inhibited DNA replication, whereas depletion of XCdc7/Dbf4 had little effect. Chromatin binding studies indicated that XCdc7/Drf1 is required for pre-replication complex activation but not their assembly. XCdc7/Dbf4 complexes bound to the chromatin in two steps: the first step was independent of pre-replication complex assembly and the second step was dependent on pre-replication complex activation. By contrast, binding of XCdc7/Drf1 complexes was entirely dependent on pre-replication complex assembly. Finally, we present evidence that the association of the two complexes on the chromatin is not regulated by ATR checkpoint pathways that result from DNA replication blocks. These data suggest that Cdc7/Drf1 but not Cdc7/Dbf4 complexes support the initiation of DNA replication in Xenopus egg extracts and during early embryonic development.In eukaryotes, initiation of DNA replication requires the assembly and activation of pre-replication complexes (pre-RCs) 5 on chromatin (1). Sequential binding to DNA of the origin recognition complex, Cdc6, Cdt1, and mini-chromosome maintenance proteins (Mcm2-7) lead to formation of pre-RCs. Pre-RC activation is under the control of two kinases, Cdk2 and Cdc7, and ultimately results in the loading of replication factors such as Cdc45 and the unwinding of replication origins by the MCM helicase complex (2-5).Cdc7 is a serine/threonine kinase that is conserved from yeast to human and is essential for cell proliferation and embryonic development (6). Like CDKs (cyclin-dependent kinases), Cdc7 activity is regulated by its association with a regulatory subunit, the Dbf4 protein. This complex is often referred to as DDK (Dbf4-dependent kinase). The existence in fission yeast of a Cdc7/Dbf4 complex paralog, Spo4/Spo6, and the recent discovery of multiple Dbf4-related molecules in animal cells suggest that they belong to a novel DDK protein kinase family (7-10

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“…Genes identified in this way are candidates for roles at replication origins S. pombe. Here, a mutation in hsk1 ϩ , which is the homolog of the S. cerevisiae CDC7 encoded serine threonine and at the replication fork and can, in principle, un-kinase, leads to a cohesion defect (Takeda et al 2001; couple the initiation of DNA replication with the establishment of sister chromatid cohesion. Bailis et al 2003).…”

Section: Discussionmentioning

confidence: 99%

The Origin Recognition Complex Links Replication, Sister Chromatid Cohesion and Transcriptional Silencing in Saccharomyces cerevisiae

et al. 2004

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Mutations in genes encoding the origin recognition complex (ORC) of Saccharomyces cerevisiae affect initiation of DNA replication and transcriptional repression at the silent mating-type loci. To explore the function of ORC in more detail, a screen for genetic interactions was undertaken using large-scale synthetic lethal analysis. Combination of orc2-1 and orc5-1 alleles with the complete set of haploid deletion mutants revealed synthetic lethal/sick phenotypes with genes involved in DNA replication, chromatin structure, checkpoints, DNA repair and recombination, and other genes that were unexpected on the basis of previous studies of ORC. Many of these genetic interactions are shared with other genes that are involved in initiation of DNA replication. Strong synthetic interactions were demonstrated with null mutations in genes that contribute to sister chromatid cohesion. A genetic interaction between orc5-1 and the cohesin mutant scc1-73 suggested that ORC function contributes to sister chromatid cohesion. Thus, comprehensive screening for genetic interactions with a replication gene revealed a connection between initiation of DNA replication and sister chromatid cohesion. Further experiments linked sister chromatid cohesion genes to silencing at mating-type loci and telomeres.

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Regulation of Initiation of S Phase, Replication Checkpoint Signaling, and Maintenance of Mitotic Chromosome Structures during S Phase by Hsk1 Kinase in the Fission Yeast

Cited by 108 publications

References 78 publications

Hsk1 kinase is required for induction of meiotic dsDNA breaks without involving checkpoint kinases in fission yeast

Hsk1 kinase is required for induction of meiotic dsDNA breaks without involving checkpoint kinases in fission yeast

Xenopus CDC7/DRF1 Complex Is Required for the Initiation of DNA Replication

The Origin Recognition Complex Links Replication, Sister Chromatid Cohesion and Transcriptional Silencing in Saccharomyces cerevisiae

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