Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4 (original) (raw)

Nature volume 446, pages 338–341 (2007)Cite this article

Abstract

CIA (CCG1-interacting factor A)/ASF1, which is the most conserved histone chaperone among the eukaryotes, was genetically identified as a factor for an anti-silencing function (Asf1)1 by yeast genetic screening. Shortly after that, the CIA–histone-H3–H4 complex was isolated from Drosophila as a histone chaperone CAF-1 stimulator2. Human CIA-I/II (ASF1a/b) was identified as a histone chaperone that interacts with the bromodomain—an acetylated-histone-recognizing domain—of CCG1, in the general transcription initiation factor TFIID3,4,5. Intensive studies have revealed that CIA/ASF1 mediates nucleosome assembly by forming a complex with another histone chaperone in human cells6 and yeast7, and is involved in DNA replication1,2, transcription4,8,9,10, DNA repair1,2,11,12 and silencing/anti-silencing1,2,8,13,14,15 in yeast. CIA/ASF1 was shown as a major storage chaperone for soluble histones in proliferating human cells6,16. Despite all these biochemical and biological functional analyses, the structure–function relationship of the nucleosome assembly/disassembly activity of CIA/ASF1 has remained elusive. Here we report the crystal structure, at 2.7 Å resolution, of CIA-I in complex with histones H3 and H4. The structure shows the histone H3–H4 dimer's mutually exclusive interactions with another histone H3–H4 dimer and CIA-I. The carboxy-terminal β-strand of histone H4 changes its partner from the β-strand in histone H2A to that of CIA-I through large conformational change. In vitro functional analysis demonstrated that CIA-I has a histone H3–H4 tetramer-disrupting activity. Mutants with weak histone H3–H4 dimer binding activity showed critical functional effects on cellular processes related to transcription. The histone H3–H4 tetramer-disrupting activity of CIA/ASF1 and the crystal structure of the CIA/ASF1–histone-H3–H4 dimer complex should give insights into mechanisms of both nucleosome assembly/disassembly and nucleosome semi-conservative replication.

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Acknowledgements

We thank T. K. Kundu for the expression vector of Xenopus histones; F. Winston for yeast strains; K. Matsubara, Y. Ikejiri, S. Okano and S. Yoshihara for the construction of the histone mutants; and K. Hasegawa for critical reading of the manuscript. This study was supported in part by the New Energy and Industrial Technology Development Organization (NEDO) of Japan, the Exploratory Research for Advanced Technology (ERATO) of the Japan Science and Technology Agency (JST), and Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author Contributions R.N. and M.E. contributed equally to this work. R.N. and Y.A. performed crystallographic and biochemical works. M.E. and N.S. performed biochemical works and yeast genetics. T.S. performed crystallographic work. M.H. and T.S. contributed to the idea, strategy, project management and writing of the manuscript. All authors discussed the results and commented on the manuscript.

The atomic coordinates have been deposited in the Protein Data Bank (PDB code, 2IO5).

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Author notes

  1. Ryo Natsume and Masamitsu Eitoku: These authors contributed equally to this work.

Authors and Affiliations

  1. Japan Biological Information Research Centre (JBIRC), Japan Biological Informatics Consortium (JBIC), 2-42 Aomi, Koto-ku, Tokyo 135-0064, Japan,
    Ryo Natsume & Yusuke Akai
  2. Laboratory of Developmental Biology, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan,
    Masamitsu Eitoku, Norihiko Sano & Masami Horikoshi
  3. Horikoshi Gene Selector Project, Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency (JST), 5-9-6 Tokodai, Tsukuba, Ibaraki 300-2635, Japan,
    Masami Horikoshi
  4. Biological Information Research Centre (BIRC), National Institute of Advanced Industrial Science and Technology (AIST), 2-42 Aomi, Koto-ku, Tokyo 135-0064, Japan,
    Toshiya Senda

Authors

  1. Ryo Natsume
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  2. Masamitsu Eitoku
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  3. Yusuke Akai
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  4. Norihiko Sano
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  5. Masami Horikoshi
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  6. Toshiya Senda
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Corresponding authors

Correspondence toMasami Horikoshi or Toshiya Senda.

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Competing interests

The atomic coordinates have been deposited in the Protein Data Bank (PDB code, 2IO5). Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Figures 1-9 with Legends, Supplementary Methods, Supplementary Tables 1-3, and additional references. (PDF 2148 kb)

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Natsume, R., Eitoku, M., Akai, Y. et al. Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4.Nature 446, 338–341 (2007). https://doi.org/10.1038/nature05613

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Editorial Summary

Nucleosome conversion

Structural conversion of the nucleosome, a minimum unit of chromatin structure made up of histones and DNA, has critical effects on DNA-mediated reactions. The mechanism of nucleosome assembly and disassembly has been elusive but now the crystal structure of a histone chaperone in complex with histones H3 and H4 has been determined.