The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation

  1. Alejandro Vaquero2,9
  1. 1Department of Genetics, the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey 08854, USA;
  2. 2Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain;
  3. 3Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA;
  4. 4Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030, USA;
  5. 5Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG), Departament de Medicina i Cirurgia Animals, Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain;
  6. 6Ageing and Cancer Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain;
  7. 7Max Planck Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, D-61231 Bad Nauheim, Germany
    1. 8 These authors contributed equally to this work.

    Abstract

    The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1–3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.

    Keywords

    Footnotes

    • 9 Corresponding authors

      E-mail avaquero{at}idibell.cat

      E-mail serrano{at}biology.rutgers.edu

    • Supplemental material is available for this article.

    • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.211342.112.

    • Received November 30, 2012.
    • Accepted February 11, 2013.
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