Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106

Dan Su; Qi Hu; Qing Li; James R. Thompson; Gaofeng Cui; Ahmed Fazly; Brian A. Davies; Maria Victoria Botuyan; Zhiguo Zhang; Georges Mer

doi:10.1038/nature10861

Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106

Dan Su, Qi Hu, Qing Li, James R. Thompson, Gaofeng Cui, Ahmed Fazly, Brian A. Davies, Maria Victoria Botuyan, Zhiguo Zhang, Georges Mer

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Abstract

Dynamic variations in the structure of chromatin influence virtually all DNA-related processes in eukaryotes and are controlled in part by post-translational modifications of histones. One such modification, the acetylation of lysine 56 (H3K56ac) in the amino-terminal α-helix (αN) of histone H3, has been implicated in the regulation of nucleosome assembly during DNA replication and repair, and nucleosome disassembly during gene transcription. In Saccharomyces cerevisiae, the histone chaperone Rtt106 contributes to the deposition of newly synthesized H3K56ac-carrying H3-H4 complex on replicating DNA, but it is unclear how Rtt106 binds H3-H4 and specifically recognizes H3K56ac as there is no apparent acetylated lysine reader domain in Rtt106. Here, we show that two domains of Rtt106 are involved in a combinatorial recognition of H3-H4. An N-terminal domain homodimerizes and interacts with H3-H4 independently of acetylation while a double pleckstrin-homology (PH) domain binds the K56-containing region of H3. Affinity is markedly enhanced upon acetylation of K56, an effect that is probably due to increased conformational entropy of the αN helix of H3. Our data support a mode of interaction where the N-terminal homodimeric domain of Rtt106 intercalates between the two H3-H4 components of the (H3-H4) ₂ tetramer while two double PH domains in the Rtt106 dimer interact with each of the two H3K56ac sites in (H3-H4) ₂. We show that the Rtt106-(H3-H4) ₂ interaction is important for gene silencing and the DNA damage response.

Original language	English (US)
Pages (from-to)	104-109
Number of pages	6
Journal	Nature
Volume	483
Issue number	7387
DOIs	https://doi.org/10.1038/nature10861
State	Published - Mar 1 2012

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@article{39f0535aacb1474481e0edfbe5e048f6,

title = "Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106",

abstract = "Dynamic variations in the structure of chromatin influence virtually all DNA-related processes in eukaryotes and are controlled in part by post-translational modifications of histones. One such modification, the acetylation of lysine 56 (H3K56ac) in the amino-terminal α-helix (αN) of histone H3, has been implicated in the regulation of nucleosome assembly during DNA replication and repair, and nucleosome disassembly during gene transcription. In Saccharomyces cerevisiae, the histone chaperone Rtt106 contributes to the deposition of newly synthesized H3K56ac-carrying H3-H4 complex on replicating DNA, but it is unclear how Rtt106 binds H3-H4 and specifically recognizes H3K56ac as there is no apparent acetylated lysine reader domain in Rtt106. Here, we show that two domains of Rtt106 are involved in a combinatorial recognition of H3-H4. An N-terminal domain homodimerizes and interacts with H3-H4 independently of acetylation while a double pleckstrin-homology (PH) domain binds the K56-containing region of H3. Affinity is markedly enhanced upon acetylation of K56, an effect that is probably due to increased conformational entropy of the αN helix of H3. Our data support a mode of interaction where the N-terminal homodimeric domain of Rtt106 intercalates between the two H3-H4 components of the (H3-H4) 2 tetramer while two double PH domains in the Rtt106 dimer interact with each of the two H3K56ac sites in (H3-H4) 2. We show that the Rtt106-(H3-H4) 2 interaction is important for gene silencing and the DNA damage response.",

author = "Dan Su and Qi Hu and Qing Li and Thompson, {James R.} and Gaofeng Cui and Ahmed Fazly and Davies, {Brian A.} and Botuyan, {Maria Victoria} and Zhiguo Zhang and Georges Mer",

note = "Funding Information: Acknowledgements We are grateful to N. Jurani{\'c}, S. Macura and T. Burghardt for experimental advice, Y. Kim for assistance with X-ray data collection, Z. Zhang for suggestions on chemical synthesis, and K. Luger and A. Hieb for advice on the preparation of histones. We acknowledge the use of synchrotron beamlines 19BM and 19ID of the Structural Biology Center at Argonne National Laboratory{\textquoteright}s APS, supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-ENG-38. This work was funded in part by National Institutes of Health grants to Z.Z. and G.M.",

year = "2012",

month = mar,

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doi = "10.1038/nature10861",

language = "English (US)",

volume = "483",

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T1 - Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106

AU - Su, Dan

AU - Hu, Qi

AU - Li, Qing

AU - Thompson, James R.

AU - Cui, Gaofeng

AU - Fazly, Ahmed

AU - Davies, Brian A.

AU - Botuyan, Maria Victoria

AU - Zhang, Zhiguo

AU - Mer, Georges

N1 - Funding Information: Acknowledgements We are grateful to N. Juranić, S. Macura and T. Burghardt for experimental advice, Y. Kim for assistance with X-ray data collection, Z. Zhang for suggestions on chemical synthesis, and K. Luger and A. Hieb for advice on the preparation of histones. We acknowledge the use of synchrotron beamlines 19BM and 19ID of the Structural Biology Center at Argonne National Laboratory’s APS, supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-ENG-38. This work was funded in part by National Institutes of Health grants to Z.Z. and G.M.

PY - 2012/3/1

Y1 - 2012/3/1

N2 - Dynamic variations in the structure of chromatin influence virtually all DNA-related processes in eukaryotes and are controlled in part by post-translational modifications of histones. One such modification, the acetylation of lysine 56 (H3K56ac) in the amino-terminal α-helix (αN) of histone H3, has been implicated in the regulation of nucleosome assembly during DNA replication and repair, and nucleosome disassembly during gene transcription. In Saccharomyces cerevisiae, the histone chaperone Rtt106 contributes to the deposition of newly synthesized H3K56ac-carrying H3-H4 complex on replicating DNA, but it is unclear how Rtt106 binds H3-H4 and specifically recognizes H3K56ac as there is no apparent acetylated lysine reader domain in Rtt106. Here, we show that two domains of Rtt106 are involved in a combinatorial recognition of H3-H4. An N-terminal domain homodimerizes and interacts with H3-H4 independently of acetylation while a double pleckstrin-homology (PH) domain binds the K56-containing region of H3. Affinity is markedly enhanced upon acetylation of K56, an effect that is probably due to increased conformational entropy of the αN helix of H3. Our data support a mode of interaction where the N-terminal homodimeric domain of Rtt106 intercalates between the two H3-H4 components of the (H3-H4) 2 tetramer while two double PH domains in the Rtt106 dimer interact with each of the two H3K56ac sites in (H3-H4) 2. We show that the Rtt106-(H3-H4) 2 interaction is important for gene silencing and the DNA damage response.

AB - Dynamic variations in the structure of chromatin influence virtually all DNA-related processes in eukaryotes and are controlled in part by post-translational modifications of histones. One such modification, the acetylation of lysine 56 (H3K56ac) in the amino-terminal α-helix (αN) of histone H3, has been implicated in the regulation of nucleosome assembly during DNA replication and repair, and nucleosome disassembly during gene transcription. In Saccharomyces cerevisiae, the histone chaperone Rtt106 contributes to the deposition of newly synthesized H3K56ac-carrying H3-H4 complex on replicating DNA, but it is unclear how Rtt106 binds H3-H4 and specifically recognizes H3K56ac as there is no apparent acetylated lysine reader domain in Rtt106. Here, we show that two domains of Rtt106 are involved in a combinatorial recognition of H3-H4. An N-terminal domain homodimerizes and interacts with H3-H4 independently of acetylation while a double pleckstrin-homology (PH) domain binds the K56-containing region of H3. Affinity is markedly enhanced upon acetylation of K56, an effect that is probably due to increased conformational entropy of the αN helix of H3. Our data support a mode of interaction where the N-terminal homodimeric domain of Rtt106 intercalates between the two H3-H4 components of the (H3-H4) 2 tetramer while two double PH domains in the Rtt106 dimer interact with each of the two H3K56ac sites in (H3-H4) 2. We show that the Rtt106-(H3-H4) 2 interaction is important for gene silencing and the DNA damage response.

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Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106

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