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SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence

Nature Structural & Molecular Biology volume 23, pages 434440 (2016) | Download Citation

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Abstract

Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing has been observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover an essential role of the human SIRT6 enzyme in pericentric transcriptional silencing, and we show that this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, residue K18 of histone H3 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, depletion of these transcripts through RNA interference rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and regulation of acetylated H3K18 at heterochromatin, and demonstrate the pathogenic role of deregulated pericentric transcription in aging- and cancer-related cellular dysfunction.

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  • 15 April 2009

    In the version of this article initially published online, acknowledgement of funding support for K.F.C. by a sponsored research agreement with Daiichi Sankyo Co., Inc. had been omitted, and a positive competing financial interest statement had not been included. The errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank O. Gozani and members of the laboratories of K.F.C. and O. Gozani for useful discussions, and S. Paredes, T. Hong, and L.D. Boxer for technical assistance. We thank X. Shi (University of Texas M.D. Anderson Cancer Center) for providing bacterial expression vectors for the AF9 YEATS domain and Z. Yang (Stanford University) for KAP1 expression vectors. This work was supported by grants from the US National Institutes of Health (NIH) to K.F.C. (R01 AG028867, R56AG050997), the Department of Veterans Affairs to K.F.C. (Merit Award), the Paul F. Glenn Laboratories for the Biology of Aging (K.F.C.), and fellowship awards to L.T. (Italian Foundation for Cancer Research fellowship abroad, American Italian Cancer Foundation postdoctoral research fellowship, and Stanford Dean's fellowship) and to Z.O. (Walter and Idun Berry postdoctoral fellowship). Work in the laboratory of W.L. was funded in part by grants from the Cancer Prevention Research Institute of Texas (RP150292) and the NIH (R01HG007538 and R01CA193466). Research of K.F.C. is partly funded by Daiichi Sankyo Co., Inc.

Author information

Affiliations

  1. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Luisa Tasselli
    • , Wei Zheng
    • , Ruth I Tennen
    • , Zaneta Odrowaz
    • , Federica Simeoni
    •  & Katrin F Chua
  2. Geriatric Research, Education, and Clinical Center, Veterans Affairs, Palo Alto Health Care System, Palo Alto, California, USA.

    • Luisa Tasselli
    • , Wei Zheng
    • , Zaneta Odrowaz
    • , Federica Simeoni
    •  & Katrin F Chua
  3. Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.

    • Yuanxin Xi
    •  & Wei Li

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Contributions

L.T. and K.F.C. conceived the project, designed the experiments and wrote the manuscript. L.T. performed in vitro and cellular deacetylation assays, ChIP and ChIP–seq experiments, RNA expression analysis, microscopy, and cell biology experiments. Y.X. and W.L. performed bioinformatic analyses for the ChIP–seq experiments and contributed to the corresponding manuscript sections. W.Z. performed ChIP experiments in KAP1-depleted cells and contributed to analysis of KAP1 in SIRT6-depleted cells. R.I.T. contributed to the deacetylation assay on H3K18ac peptides, analysis of satellite transcripts, and manuscript editing. Z.O. performed ChIP experiments in SIRT6-overexpressing cells. F.S. purified nucleosomes for deacetylation assays.

Competing interests

Research of K.F.C. is partly funded by Daiichi Sankyo Co., Inc.

Corresponding authors

Correspondence to Wei Li or Katrin F Chua.

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https://doi.org/10.1038/nsmb.3202

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