Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice

ELife
Shrestha GhoshZhongjun Zhou

Abstract

Mammalian sirtuin 6 (Sirt6) is a conserved NAD+-dependent deacylase and mono-ADP ribosylase that is known to be involved in DNA damage repair, metabolic homeostasis, inflammation, tumorigenesis, and aging. Loss of Sirt6 in mice results in accelerated aging and premature death within a month. Here, we show that haploinsufficiency (i.e., heterozygous deletion) of Trp53 dramatically extends the lifespan of both female and male Sirt6-deficient mice. Haploinsufficiency of Trp53 in Sirt6-deficient mice rescues several age-related phenotypes of Sirt6-deficient mice, including reduced body size and weight, lordokyphosis, colitis, premature senescence, apoptosis, and bone marrow stem cell decline. Mechanistically, SIRT6 deacetylates p53 at lysine 381 to negatively regulate the stability and activity of p53. These findings establish that elevated p53 activity contributes significantly to accelerated aging in Sirt6-deficient mice. Our study demonstrates that p53 is a substrate of SIRT6, and highlights the importance of SIRT6-p53 axis in the regulation of aging.

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Citations

Aug 23, 2019·Physiological Reviews·Andrew R ChangRaul Mostoslavsky
Aug 14, 2020·Nucleic Acids Research·Anke GengZhiyong Mao
Jun 15, 2019·Journal of Experimental & Clinical Cancer Research : CR·Jie ZhaoZhuan Li
Sep 22, 2018·Cell Death & Disease·Meiting LiWei-Guo Zhu
Sep 12, 2020·Aging·Huafang WeiWei Li
Mar 16, 2019·Current Opinion in Chemical Biology·Tatsiana KosciukHening Lin
Apr 14, 2021·Annual Review of Biochemistry·Miao Wang, Hening Lin
Feb 23, 2020·Journal of Proteome Research·Paula A Agudelo GarciaMark R Parthun

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Methods Mentioned

BETA
acetylation
acetylations
X-ray
flow cytometry
co-immunoprecipitation
pull down
transfection
genotyping
PCR
gel-filtration

Software Mentioned

ZEN
Image J
GraphPad Prism

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