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Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

Author

Listed:
  • Shin-ichiro Imai

    (Massachusetts Institute of Technology)

  • Christopher M. Armstrong

    (Massachusetts Institute of Technology)

  • Matt Kaeberlein

    (Massachusetts Institute of Technology)

  • Leonard Guarente

    (Massachusetts Institute of Technology)

Abstract

Yeast Sir2 is a heterochromatin component that silences transcription at silent mating loci1, telomeres2 and the ribosomal DNA3,4, and that also suppresses recombination in the rDNA5 and extends replicative life span6. Mutational studies indicate that lysine 16 in the amino-terminal tail of histone H4 and lysines 9, 14 and 18 in H3 are critically important in silencing, whereas lysines 5, 8 and 12 of H4 have more redundant functions7,8,9. Lysines 9 and 14 of histone H3 and lysines 5, 8 and 16 of H4 are acetylated in active chromatin and hypoacetylated in silenced chromatin, and overexpression of Sir2 promotes global deacetylation of histones9,10, indicating that Sir2 may be a histone deacetylase. Deacetylation of lysine 16 of H4 is necessary for binding the silencing protein, Sir3 (ref. 8). Here we show that yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases, which deacetylate lysines 9 and 14 of H3 and specifically lysine 16 of H4. Our analysis of two SIR2 mutations supports the idea that this deacetylase activity accounts for silencing, recombination suppression and extension of life span in vivo. These findings provide a molecular framework of NAD-dependent histone deacetylation that connects metabolism, genomic silencing and ageing in yeast and, perhaps, in higher eukaryotes.

Suggested Citation

  • Shin-ichiro Imai & Christopher M. Armstrong & Matt Kaeberlein & Leonard Guarente, 2000. "Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase," Nature, Nature, vol. 403(6771), pages 795-800, February.
  • Handle: RePEc:nat:nature:v:403:y:2000:i:6771:d:10.1038_35001622
    DOI: 10.1038/35001622
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    Cited by:

    1. Björn Klabunde & André Wesener & Wilhelm Bertrams & Isabell Beinborn & Nicole Paczia & Kristin Surmann & Sascha Blankenburg & Jochen Wilhelm & Javier Serrania & Kèvin Knoops & Eslam M. Elsayed & Katri, 2023. "NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Shuai Zhang & Zhe Sun & Yuewen Qi & Xiaolu Fang & Hong Yu, 2018. "Prognostic and Clinicopathological Value of SIRT1 Expression in Female Reproductive System Cancer," International Journal of Sciences, Office ijSciences, vol. 7(01), pages 57-65, January.
    3. Beata Jablonska & Katrina L. Adams & Panagiotis Kratimenos & Zhen Li & Emma Strickland & Tarik F. Haydar & Katharina Kusch & Klaus-Armin Nave & Vittorio Gallo, 2022. "Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Xiangkai Zhen & Biao Zhou & Zihe Liu & Xurong Wang & Heyu Zhao & Shuxian Wu & Zekai Li & Jiamin liang & Wanyue Zhang & Qingjian Zhu & Jun He & Xiaoli Xiong & Songying Ouyang, 2024. "Mechanistic basis for the allosteric activation of NADase activity in the Sir2-HerA antiphage defense system," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Xiangkai Zhen & Xiaolong Xu & Le Ye & Song Xie & Zhijie Huang & Sheng Yang & Yanhui Wang & Jinyu Li & Feng Long & Songying Ouyang, 2024. "Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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