See also: C Cosentino & R Mostoslavsky (July 2014)
SIRT2 induces the checkpoint kinase BubR1 to increase lifespan
Article first published online: 13 MAY 2014
© 2014 The Authors
The EMBO Journal
Volume 33, Issue 13, pages 1438–1453, 1 July 2014
How to Cite
The EMBO Journal (2014) 33: 1438–1453
- Issue published online: 1 JUL 2014
- Article first published online: 13 MAY 2014
- Manuscript Accepted: 9 MAR 2014
- Manuscript Revised: 22 JAN 2014
- Manuscript Received: 16 SEP 2013
- NIH/NIA. Grant Numbers: R01 AG028730, RO1 AG019719
- Glenn Foundation for Medical Research
- United Mitochondrial Disease Foundation
- The Juvenile Diabetes foundation
- BIDMC/Harvard Translational Research. Grant Number: T32 AG023480
- Leducq Foundation Network of Research Excellence
- NAD + ;
Mice overexpressing the mitotic checkpoint kinase gene BubR1 live longer, whereas mice hypomorphic for BubR1 (BubR1H/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 BubR1H/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.
The checkpoint kinase BubR1 declines in aging mice, and its overexpression increases lifespan. The NAD+-dependent deacetylase Sirt2 deacetylates BubR1, increasing its abundance and the lifespan of progeroid BubR1H/H mice.
- BubR1 encodes a mitotic checkpoint kinase, levels of which determine the pace of aging.
- The abundance of BubR1 is controlled by acetylation of lysine 668.
- BubR1 acetylation is regulated by the acetyltransferase CBP and the NAD+-dependent deacetylase SIRT2.
- Overexpression of SIRT2 or treatment with the NAD precursor NMN stabilizes BubR1 in vivo.
- Overexpression of SIRT2 in progeroid BubR1 hypomorphs improves cardiac function and extends lifespan.