SIRT2 induces the checkpoint kinase BubR1 to increase lifespan

EMBO J. 2014 Jul 1;33(13):1438-53. doi: 10.15252/embj.201386907. Epub 2014 May 12.

Abstract

Mice overexpressing the mitotic checkpoint kinase gene BubR1 live longer, whereas mice hypomorphic for BubR1 (BubR1(H/H)) live shorter and show signs of accelerated aging. As wild-type mice age, BubR1 levels decline in many tissues, a process that is proposed to underlie normal aging and age-related diseases. Understanding why BubR1 declines with age and how to slow this process is therefore of considerable interest. The sirtuins (SIRT1-7) are a family of NAD(+)-dependent deacetylases that can delay age-related diseases. Here, we show that the loss of BubR1 levels with age is due to a decline in NAD(+) and the ability of SIRT2 to maintain lysine-668 of BubR1 in a deacetylated state, which is counteracted by the acetyltransferase CBP. Overexpression of SIRT2 or treatment of mice with the NAD(+) precursor nicotinamide mononucleotide (NMN) increases BubR1 abundance in vivo. Overexpression of SIRT2 in BubR1(H/H) animals increases median lifespan, with a greater effect in male mice. Together, these data indicate that further exploration of the potential of SIRT2 and NAD(+) to delay diseases of aging in mammals is warranted.

Keywords: BubR1; NAD +; acetylation; aging; sirtuin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Enzyme Induction / physiology
  • HeLa Cells
  • Humans
  • Longevity / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • NAD / genetics
  • NAD / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sirtuin 2 / genetics
  • Sirtuin 2 / metabolism*

Substances

  • Bub1b protein, mouse
  • Cell Cycle Proteins
  • NAD
  • BUB1 protein, human
  • Protein-Serine-Threonine Kinases
  • SIRT2 protein, human
  • Sirt2 protein, mouse
  • Sirtuin 2