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Structural plasticity of histones H3–H4 facilitates their allosteric exchange between RbAp48 and ASF1

Abstract

The mechanisms by which histones are disassembled and reassembled into nucleosomes and chromatin structure during DNA replication, repair and transcription are poorly understood. A better understanding of the processes involved is, however, crucial if we are to understand whether and how histone variants and post-translationally modified histones are inherited in an epigenetic manner. To this end we have studied the interaction of the histone H3–H4 complex with the human retinoblastoma-associated protein RbAp48 and their exchange with a second histone chaperone, anti-silencing function protein 1 (ASF1). Exchange of histones H3–H4 between these two histone chaperones has a central role in the assembly of new nucleosomes, and we show here that the H3–H4 complex has an unexpected structural plasticity, which is important for this exchange.

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Figure 1: Stoichiometry of the RbAp48 interaction with the histone H3–H4 complex.
Figure 2: RbAp48 binds to histone H3–H4 dimers.
Figure 3: The H3–H4 complex undergoes substantial structural rearrangement upon binding of RbAp48.
Figure 4: Both RbAp48 and ASF1 can simultaneously bind the histone H3–H4 complex.
Figure 5: Comparison of the affinities of ASF1 for the histone H3–H4 and RbAp48–H3–H4 complexes.

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Acknowledgements

We thank I. Berger (European Molecular Biology Laboratory, Grenoble, France) for insect cell expression vectors, R. Marmostein (Wistar Institute, Philadelphia, USA) for the plasmid expressing human ASF11–159, K. Luger (Colorado State University, Fort Collins, Colorado, USA) for advice on suitable buffers for fluorescence experiments, S. McLaughlin and N. Royle for purification of preliminary samples of histones H3–H4 and ASF1, A. Murzin for helpful discussions and comments on the manuscript, the Protein & Nucleic Acid Chemistry Facility (PNAC; Department of Biochemistry, University of Cambridge), and J. McCullagh and C. Schofield (Chemistry Department, University of Oxford, UK) for access to the Synapt instrument for nondenaturing MS experiments. We thank the Wellcome Trust, the Engineering and Physical Sciences Research Council (EPSRC) and the Biotechnology and Biological Sciences Research Council (BBSRC) for their support of this research: 082010/Z/07/Z (E.D.L., N.V.M.) 092441/Z/10/Z (A.A.W.), BB/D526088/1 (M.T.), EC FP7 277899 (E.D.L., F.S.), BB/E022286/1 (D.G.N., R.W.).

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W.Z., M.T., R.W., F.S., J.M., A.A.W. and O.F. performed experiments. A.S.M. expressed recombinant RbAp48 protein. A.B., T.O.-H., H.E.M., N.V.M. and D.G.N. provided technical and conceptual advice. E.D.L. supervised the work and prepared the manuscript, with assistance from the other authors.

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Correspondence to Ernest D Laue.

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Zhang, W., Tyl, M., Ward, R. et al. Structural plasticity of histones H3–H4 facilitates their allosteric exchange between RbAp48 and ASF1. Nat Struct Mol Biol 20, 29–35 (2013). https://doi.org/10.1038/nsmb.2446

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