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

Nature Cell Biology volume 11, pages 357–362 (2009)Cite this article

Abstract

Heterochromatin is a structurally compacted region of chromosomes in which transcription and recombination are inactivated1,2. DNA replication is temporally regulated in heterochromatin, but the molecular mechanism for regulation has not been elucidated. Among heterochromatin loci in Schizosaccharomyces pombe, the pericentromeric region and the silent mating-type (mat) locus replicate in early S phase, whereas the sub-telomeric region does not3,4,5, suggesting complex mechanisms for regulation of replication in heterochromatic regions. Here, we show that Swi6, an S. pombe counterpart of heterochromatin protein 1 (HP1), is required for early replication of the pericentromeric region and the mat locus. Origin-loading of Sld3, which depends on Dfp1/Dbf4-dependent kinase Cdc7 (DDK), is stimulated by Swi6. An HP1-binding motif within Dfp1 is required for interaction with Swi6 in vitro and for early replication of the pericentromeric region and mat locus. Tethering of Dfp1 to the pericentromeric region and mat locus in swi6-deficient cells restores early replication of these loci. Our results show that a heterochromatic protein positively regulates initiation of replication in silenced chromatin by interacting with an essential kinase.

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Figure 1: Swi6 promotes firing of origins in early S phase specifically at the pericentromeric region and matK.
Figure 2: Swi6 stimulates loading of Sld3 at the pericentromeric region and matK.
Figure 3: Point-mutations in the HP1-binding motif of Dfp1 decrease its in vitro interaction with Swi6 and delay replication at the pericentromeric region and matK in vivo.
Figure 4: Tethering Dfp1 to heterochromatin accelerates replication timing independently of Swi6 localization.
Figure 5: A model for the regulation of replication origins in heterochromatic loci.

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References

  1. Moazed, D. Common themes in mechanisms of gene silencing. Mol. Cell 8, 489–498 (2001).

    Article  CAS  Google Scholar 

  2. Peng, J. C. & Karpen, G. H. Epigenetic regulation of heterochromatic DNA stability. Curr. Opin. Genet. Dev. 18, 204–211 (2008).

    Article  CAS  Google Scholar 

  3. Hayashi, M. et al. Genome-wide localization of pre-RC sites and identification of replication origins in fission yeast. EMBO J. 26, 1327–1339 (2007).

    Article  CAS  Google Scholar 

  4. Kim, S. M., Dubey, D. D. & Huberman, J. A. Early-replicating heterochromatin. Genes Dev. 17, 330–335 (2003).

    Article  CAS  Google Scholar 

  5. Kim, S. M. & Huberman, J. A. Regulation of replication timing in fission yeast. EMBO J. 20, 6115–6126 (2001).

    Article  CAS  Google Scholar 

  6. Gilbert, D. M. Replication timing and transcriptional control: beyond cause and effect. Curr. Opin. Cell Biol. 14, 377–383 (2002).

    Article  CAS  Google Scholar 

  7. Aladjem, M. I. Replication in context: dynamic regulation of DNA replication patterns in metazoans. Nature Rev. Genet. 8, 588–600 (2007).

    Article  CAS  Google Scholar 

  8. Grewal, S. I. & Jia, S. Heterochromatin revisited. Nature Rev. Genet. 8, 35–46 (2007).

    Article  CAS  Google Scholar 

  9. Nakayama, J., Klar, A. J. & Grewal, S. I. A chromodomain protein, Swi6, performs imprinting functions in fission yeast during mitosis and meiosis. Cell 101, 307–317 (2000).

    Article  CAS  Google Scholar 

  10. Klar, A. J. & Bonaduce, M. J. swi6, a gene required for mating-type switching, prohibits meiotic recombination in the mat2-mat3 “cold spot” of fission yeast. Genetics 129, 1033–1042 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Nakayama, J., Allshire, R. C., Klar, A. J. & Grewal, S. I. A role for DNA polymerase alpha in epigenetic control of transcriptional silencing in fission yeast. EMBO J. 20, 2857–2866 (2001).

    Article  CAS  Google Scholar 

  12. Ahmed, S., Saini, S., Arora, S. & Singh, J. Chromodomain protein Swi6-mediated role of DNA polymerase alpha in establishment of silencing in fission yeast. J. Biol. Chem. 276, 47814–47821 (2001).

    Article  CAS  Google Scholar 

  13. Bailis, J. M., Bernard, P., Antonelli, R., Allshire, R. C. & Forsburg, S. L. Hsk1-Dfp1 is required for heterochromatin-mediated cohesion at centromeres. Nature Cell Biol. 5, 1111–1116 (2003).

    Article  CAS  Google Scholar 

  14. Smith, J. G. et al. Replication of centromere II of Schizosaccharomyces pombe. Mol. Cell Biol. 15, 5165–5172 (1995).

    Article  CAS  Google Scholar 

  15. Olsson, T., Ekwall, K. & Ruusala, T. The silent P mating type locus in fission yeast contains two autonomously replicating sequences. Nucleic Acids Res. 21, 855–861 (1993).

    Article  CAS  Google Scholar 

  16. Jacobs, S. A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083 (2002).

    Article  CAS  Google Scholar 

  17. Yabuuchi, H. et al. Ordered assembly of Sld3, GINS and Cdc45 is distinctly regulated by DDK and CDK for activation of replication origins. EMBO J. 25, 4663–4674 (2006).

    Article  CAS  Google Scholar 

  18. Yamada, Y., Nakagawa, T. & Masukata, H. A novel intermediate in initiation complex assembly for fission yeast DNA replication. Mol. Biol. Cell 15, 3740–3750 (2004).

    Article  CAS  Google Scholar 

  19. Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D. & Grewal, S. I. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292, 110–113 (2001).

    Article  CAS  Google Scholar 

  20. Hall, I. M. et al. Establishment and maintenance of a heterochromatin domain. Science 297, 2232–2237 (2002).

    Article  CAS  Google Scholar 

  21. Sadaie, M., Iida, T., Urano, T. & Nakayama, J. A chromodomain protein, Chp1, is required for the establishment of heterochromatin in fission yeast. EMBO J. 23, 3825–3835 (2004).

    Article  CAS  Google Scholar 

  22. Cam, H. P. et al. Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. Nature Genet. 37, 809–819 (2005).

    Article  CAS  Google Scholar 

  23. Kanoh, J., Sadaie, M., Urano, T. & Ishikawa, F. Telomere binding protein Taz1 establishes Swi6 heterochromatin independently of RNAi at telomeres. Curr. Biol. 15, 1808–1819 (2005).

    Article  CAS  Google Scholar 

  24. Kawashima, S. A. et al. Shugoshin enables tension-generating attachment of kinetochores by loading Aurora to centromeres. Genes Dev. 21, 420–435 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Hiroyuki Araki for critical reading and Yoshinori Watanabe for providing CFP-chromodomain constructs. M.T.H. is a Research Fellow of the Japan Society for the Promotion of Science. This study was supported by a Grant-in-Aid for JSPS Fellows to M.T.H., and in part by a Grant-in-Aid to H.M. and to J.N. from the Ministry of Education, Science, Technology, Sports and Culture, Japan.

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Authors and Affiliations

  1. Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, 560-0043, Osaka, Japan

    Makoto T. Hayashi, Tatsuro S. Takahashi, Takuro Nakagawa & Hisao Masukata

  2. Laboratory for Chromatin Dynamics, Center for Developmental Biology, RIKEN, Kobe, 650-0047, Japan

    Jun-ichi Nakayama

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  1. Makoto T. Hayashi
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  2. Tatsuro S. Takahashi
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  3. Takuro Nakagawa
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  5. Hisao Masukata
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Contributions

M.T.H. and H.M. designed the project and wrote the paper; M.T.H. performed the experiments; J.N. provided important experimental materials and advice. All authors contributed to the interpretation of the results and edited the manuscript.

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Correspondence to Hisao Masukata.

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Hayashi, M., Takahashi, T., Nakagawa, T. et al. The heterochromatin protein Swi6/HP1 activates replication origins at the pericentromeric region and silent mating-type locus. Nat Cell Biol 11, 357–362 (2009). https://doi.org/10.1038/ncb1845

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