Nucleosome flipping drives kinetic proofreading and processivity by SWR1

Paul Girvan, Adam S. B. Jalal, Elizabeth A. McCormack, Michael T. Skehan, Carol L. Knight, Dale B. Wigley () and David S. Rueda ()
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Paul Girvan: Imperial College London
Adam S. B. Jalal: Imperial College London
Elizabeth A. McCormack: Imperial College London
Michael T. Skehan: Imperial College London
Carol L. Knight: Imperial College London
Dale B. Wigley: Imperial College London
David S. Rueda: MRC Laboratory of Medical Sciences

Nature, 2024, vol. 636, issue 8041, 251-257

Abstract: Abstract The yeast SWR1 complex catalyses the exchange of histone H2A–H2B dimers in nucleosomes, with Htz1–H2B dimers1–3. Here we used single-molecule analysis to demonstrate two-step double exchange of the two H2A–H2B dimers in a canonical yeast nucleosome with Htz1–H2B dimers, and showed that double exchange can be processive without release of the nucleosome from the SWR1 complex. Further analysis showed that bound nucleosomes flip between two states, with each presenting a different face, and hence histone dimer, to SWR1. The bound dwell time is longer when an H2A–H2B dimer is presented for exchange than when presented with an Htz1–H2B dimer. A hexasome intermediate in the reaction is bound to the SWR1 complex in a single orientation with the ‘empty’ site presented for dimer insertion. Cryo-electron microscopy analysis revealed different populations of complexes showing nucleosomes caught ‘flipping’ between different conformations without release, each placing a different dimer into position for exchange, with the Swc2 subunit having a key role in this process. Together, the data reveal a processive mechanism for double dimer exchange that explains how SWR1 can ‘proofread’ the dimer identities within nucleosomes.

Date: 2024
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DOI: 10.1038/s41586-024-08152-y

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