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Shan CM, Kim JK, Wang J, et al. The histone H3K9M mutation synergizes with H3K14 ubiquitylation to selectively sequester histone H3K9 methyltransferase Clr4 at heterochromatin. Cell Rep. 2021;35(7):109137doi: 10.1016/j.celrep.2021.109137.
Shan, C. M., Kim, J. K., Wang, J., Bao, K., Sun, Y., Chen, H., Yue, J. X., Stirpe, A., Zhang, Z., Lu, C., Schalch, T., Liti, G., Nagy, P. L., Tong, L., Qiao, F., & Jia, S. (2021). The histone H3K9M mutation synergizes with H3K14 ubiquitylation to selectively sequester histone H3K9 methyltransferase Clr4 at heterochromatin. Cell reports, 35(7), 109137. https://doi.org/10.1016/j.celrep.2021.109137
Shan, Chun-Min, et al. "The histone H3K9M mutation synergizes with H3K14 ubiquitylation to selectively sequester histone H3K9 methyltransferase Clr4 at heterochromatin." Cell reports vol. 35,7 (2021): 109137. doi: https://doi.org/10.1016/j.celrep.2021.109137
Shan CM, Kim JK, Wang J, Bao K, Sun Y, Chen H, Yue JX, Stirpe A, Zhang Z, Lu C, Schalch T, Liti G, Nagy PL, Tong L, Qiao F, Jia S. The histone H3K9M mutation synergizes with H3K14 ubiquitylation to selectively sequester histone H3K9 methyltransferase Clr4 at heterochromatin. Cell Rep. 2021 May 18;35(7):109137. doi: 10.1016/j.celrep.2021.109137. PMID: 34010645; PMCID: PMC8167812.
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Cell Rep. 2021 May 18;35(7):109137. doi: 10.1016/j.celrep.2021.109137.

The histone H3K9M mutation synergizes with H3K14 ubiquitylation to selectively sequester histone H3K9 methyltransferase Clr4 at heterochromatin.

Cell reports

Chun-Min Shan, Jin-Kwang Kim, Jiyong Wang, Kehan Bao, Yadong Sun, Huijie Chen, Jia-Xing Yue, Alessandro Stirpe, Zhiguo Zhang, Chao Lu, Thomas Schalch, Gianni Liti, Peter L Nagy, Liang Tong, Feng Qiao, Songtao Jia

Affiliations

  1. Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  2. Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
  3. Department of Pathology, Columbia University, New York, NY 10068, USA.
  4. Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice 06107, France.
  5. Leicester Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, UK.
  6. Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
  7. Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
  8. Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: [email protected].

PMID: 34010645 PMCID: PMC8167812 DOI: 10.1016/j.celrep.2021.109137

Abstract

Oncogenic histone lysine-to-methionine mutations block the methylation of their corresponding lysine residues on wild-type histones. One attractive model is that these mutations sequester histone methyltransferases, but genome-wide studies show that mutant histones and histone methyltransferases often do not colocalize. Using chromatin immunoprecipitation sequencing (ChIP-seq), here, we show that, in fission yeast, even though H3K9M-containing nucleosomes are broadly distributed across the genome, the histone H3K9 methyltransferase Clr4 is mainly sequestered at pericentric repeats. This selective sequestration of Clr4 depends not only on H3K9M but also on H3K14 ubiquitylation (H3K14ub), a modification deposited by a Clr4-associated E3 ubiquitin ligase complex. In vitro, H3K14ub synergizes with H3K9M to interact with Clr4 and potentiates the inhibitory effects of H3K9M on Clr4 enzymatic activity. Moreover, binding kinetics show that H3K14ub overcomes the Clr4 aversion to H3K9M and reduces its dissociation. The selective sequestration model reconciles previous discrepancies and demonstrates the importance of protein-interaction kinetics in regulating biological processes.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Conflict of interest statement

Declaration of interests The authors declare no competing interest.

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