The heterochromatin protein Swi6/HP1 activates replication origins at the pericentromeric region and silent mating-type locus

Hayashi, Makoto; Takahashi, Tatsuro; Nakagawa, Takuro; Nakayama, Jun‐ichi; Masukata, Hisao

doi:10.1038/ncb1845

Cited by 142 publications

(201 citation statements)

References 24 publications

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“…We also identified peptides, albeit few, corresponding to previously described Swi6-associated proteins, such as JmjC protein Epe1 (38, 39), Hsk1-Dfp1 (40,41), and Pcr1 involved in heterochromatic silencing (42). Also detected were peptides representing different subunits of SHREC (Fig.…”

Section: Swi6mentioning

confidence: 86%

“…Additional work is required to confirm their interaction with Swi6. Chromatin remodelling factors Ino80 and RSC might not be required for silencing at heterochromatic loci, but it is possible that Swi6 partners with these factors to exert control over other chromosomal processes (41). While this work was under review, another independent study described purifications of S. pombe HP1 proteins (59).…”

Section: Discussionmentioning

confidence: 99%

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Diverse roles of HP1 proteins in heterochromatin assembly and functions in fission yeast

Fischer

Cui

Dhakshnamoorthy

et al. 2009

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

133

175

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Section: Swi6mentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Diverse roles of HP1 proteins in heterochromatin assembly and functions in fission yeast

Fischer

Cui

Dhakshnamoorthy

et al. 2009

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

133

175

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“…Functional dissection of Schizosaccaromyces pombe Dfp1 identifies separate regions that are required for checkpoint response (N-terminal domain; Takeda et al 1999;Fung et al 2002), for centromere cohesion and replication (MIR domain; Bailis et al 2003;Hayashi et al 2009) and for proper response to alkylation damage during S phase (C-terminal domain; Takeda et al 1999;Fung et al 2002). Recent studies indicate that the DDK kinase is required for initiation of programmed double-strand breaks in meiosis (Sasanuma et al 2008;Wan et al 2008) and meiotic chromosome orientation (Lo et al 2008;Matos et al 2008).…”

mentioning

confidence: 99%

Fission Yeast Hsk1 (Cdc7) Kinase Is Required After Replication Initiation for Induced Mutagenesis and Proper Response to DNA Alkylation Damage

Dolan

Schmidt

et al. 2010

Genetics

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Genome stability in fission yeast requires the conserved S-phase kinase Hsk1 (Cdc7) and its partner Dfp1 (Dbf4). In addition to their established function in the initiation of DNA replication, we show that these proteins are important in maintaining genome integrity later in S phase and G2. hsk1 cells suffer increased rates of mitotic recombination and require recombination proteins for survival. Both hsk1 and dfp1 mutants are acutely sensitive to alkylation damage yet defective in induced mutagenesis. Hsk1 and Dfp1 are associated with the chromatin even after S phase, and normal response to MMS damage correlates with the maintenance of intact Dfp1 on chromatin. A screen for MMS-sensitive mutants identified a novel truncation allele, rad35 (dfp1-(1-519)), as well as alleles of other damage-associated genes. Although Hsk1-Dfp1 functions with the Swi1-Swi3 fork protection complex, it also acts independently of the FPC to promote DNA repair. We conclude that Hsk1-Dfp1 kinase functions post-initiation to maintain replication fork stability, an activity potentially mediated by the C terminus of Dfp1.T HE Hsk1 protein kinase, the fission yeast ortholog of Saccharomyces cerevisiae Cdc7, is a conserved protein essential for the initiation of DNA replication (Masai et al. 1995;Brown and Kelly 1998;Snaith et al. 2000). Data from many systems suggest that the kinase functions at individual replication origins to activate the prereplication complex (preRC) through phosphorylation of the MCM helicase and other subunits (reviewed in Forsburg 2004). In fission yeast, Hsk1 kinase activity is limited to S phase by its regulatory subunit Dfp1, which is transcriptionally and posttranslationally regulated to restrict its peak of activity to S phase (Brown and Kelly 1999;Takeda et al. 1999). The requirement for Dfp1 (in S. cerevisiae, Dbf4) is similar to the dependence of CDK kinases on cyclin activity; thus, the Ccd7 kinase family has been dubbed DDK (Dbf4-dependent kinases) ( Johnston et al. 1999;Duncker and Brown 2003). Hsk1 is a target of the Cds1 checkpoint kinase and undergoes Cds1-dependent phosphorylation during hydroxyurea (HU) treatment in vivo and in vitro (Snaith et al. 2000). Interestingly, deletion of Dcds1 partly rescues hsk1-1312 temperature sensitivity, which suggests that Hsk1 is negatively regulated by the replication checkpoint. In turn, Cds1 is poorly activated in hsk1 mutants after HU treatment, indicating that there may be a feedback loop linking these two kinases (Snaith et al. 2000;Takeda et al. 2001). hsk1 mutants are sensitive to HU treatment, with a phenotype suggesting a specific defect in recovery (Snaith et al. 2000).DDK kinases have substrates outside of the replication initiation pathway. Functional dissection of Schizosaccaromyces pombe Dfp1 identifies separate regions that are required for checkpoint response (N-terminal domain; Takeda et al. 1999;Fung et al. 2002), for centromere cohesion and replication (MIR domain;Bailis et al. 2003;Hayashi et al. 2009) and for proper response to alkylat...

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“…This might indicate a role for HP1 in recruiting the ORC to chromatin. In Schizosaccharomyces pombe, an organism with rather unusual early replication of heterochromatin (Kim et al 2003), HP1 has recently been suggested to activate replication origins by recruiting the Dfp1 (Dbf4)-dependent kinase (DDK) to origins within pericentromeres and the silent mating-type locus (Hayashi et al 2009). …”

mentioning

confidence: 99%

Heterochromatin protein 1 (HP1) modulates replication timing of the Drosophila genome

Schwaiger¹,

Kohler²,

Oakeley³

et al. 2010

Genome Res.

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The replication of a chromosomal region during S phase can be highly dynamic between cell types that differ in transcriptome and epigenome. Early replication timing has been positively correlated with several histone modifications that occur at active genes, while repressive histone modifications mark late replicating regions. This raises the question if chromatin modulates the initiating events of replication. To gain insights into this question, we have studied the function of heterochromatin protein 1 (HP1), which is a reader of repressive methylation at histone H3 lysine 9, in genome-wide organization of replication. Cells with reduced levels of HP1 show an advanced replication timing of centromeric repeats in agreement with the model that repressive chromatin mediates the very late replication of large clusters of constitutive heterochromatin. Surprisingly, however, regions with high levels of interspersed repeats on the chromosomal arms, in particular on chromosome 4 and in pericentromeric regions of chromosome 2, behave differently. Here, loss of HP1 results in delayed replication. The fact that these regions are bound by HP1 suggests a direct effect. Thus while HP1 mediates very late replication of centromeric DNA, it is also required for early replication of euchromatic regions with high levels of repeats. This observation of opposing functions of HP1 suggests a model where HP1-mediated repeat inactivation or replication complex loading on the chromosome arms is required for proper activation of origins of replication that fire early. At the same time, HP1-mediated repression at constitutive heterochromatin is required to ensure replication of centromeric repeats at the end of S phase.

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The heterochromatin protein Swi6/HP1 activates replication origins at the pericentromeric region and silent mating-type locus

Cited by 142 publications

References 24 publications

Diverse roles of HP1 proteins in heterochromatin assembly and functions in fission yeast

Diverse roles of HP1 proteins in heterochromatin assembly and functions in fission yeast

Fission Yeast Hsk1 (Cdc7) Kinase Is Required After Replication Initiation for Induced Mutagenesis and Proper Response to DNA Alkylation Damage

Heterochromatin protein 1 (HP1) modulates replication timing of the Drosophila genome

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