Abstract
Histone variant H2A.Z has a conserved role in genome stability, although it remains unclear how this is mediated. Here we demonstrate that the fission yeast Swr1 ATPase inserts H2A.Z (Pht1) into chromatin and Kat5 acetyltransferase (Mst1) acetylates it. Deletion or an unacetylatable mutation of Pht1 leads to genome instability, primarily caused by chromosome entanglement and breakage at anaphase. This leads to the loss of telomere-proximal markers, though telomere protection and repeat length are unaffected by the absence of Pht1. Strikingly, the chromosome entanglement in pht1Δ anaphase cells can be rescued by forcing chromosome condensation before anaphase onset. We show that the condensin complex, required for the maintenance of anaphase chromosome condensation, prematurely dissociates from chromatin in the absence of Pht1. This and other findings suggest an important role for H2A.Z in the architecture of anaphase chromosomes.
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Acknowledgements
We thank R. Allshire (Univ. of Edinburgh), M. Bühler (Friedrich Miescher Institute for Biomedical Research), J. Cooper (Cancer Research UK), D. Finley (Harvard Medical School), S. Forsburg (Univ. of Southern California, Los Angeles), K. Gull (Univ. of Oxford), C. Hoffmann (Boston College), J. Kanoh (Kyoto Univ.), R. Maraia (NIH), D. Moazed (Harvard Medical School), T. Nakamura (Univ. of Illinois at Chicago), F. Neumann (Rockefeller Univ.), P. Nurse (Rockefeller Univ.), M. O'Connell (Mount Sinai School of Medicine), J. Partridge (St. Judes Children's Research Hospital), M. Yanagida (Kyoto Univ.) and the Yeast Genome Resource Center (Osaka City Univ.) for the generous supply of antibodies and yeast strains (detailed in Supplementary Tables 3 and 4). We also thank G. Zhong, S. Chandran, T. Punna and M. Shales for technical support. Finally, we are grateful to G. Ingram for expertise with the Telomere Repeat Length assay. Work in the J.B. lab is funded by Cancer Research UK, T.K. lab by a start-up grant from the Ontario Cancer Institute, K.G.H. lab by a program grant from the Wellcome Trust and M.-C.K. lab by an NCI Cancer Center Support grant to Albert Einstein College of Medicine (2P30CA013330) and the Speaker's Fund for Biomedical Research: Toward the Science of Patient Care, awarded by the City of New York.
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H.-S.K. was responsible for the data in Figure 1 (with A.T. contributing Fig. 1c), Figure 2 (with MS help from J.F., T.K., A.E. and J.F.G.), Figures 5c and 5d and Supplementary Figures 1 and 3. V.V. (with help from K.G.H.) was responsible for the data in Figures 4 and 5a–c and Supplementary Figures 2, 3a and 4. S.W. and J.B. performed and analyzed the microarrays in Figures 3a and 3b; A.R. and N.J.K. performed and analyzed the genetic screens in Figures 3c–f. L.R.C. and C.S.B. created the antibodies to Pht1 used in Figure 1. H.-S.K., V.V. and M.-C.K. planned experiments, analyzed the data and wrote the manuscript.
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Kim, HS., Vanoosthuyse, V., Fillingham, J. et al. An acetylated form of histone H2A.Z regulates chromosome architecture in Schizosaccharomyces pombe. Nat Struct Mol Biol 16, 1286–1293 (2009). https://doi.org/10.1038/nsmb.1688
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DOI: https://doi.org/10.1038/nsmb.1688
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