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

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,...

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Autores principales: Ghosh, Shrestha, Wong, Sheung Kin, Jiang, Zhixin, Liu, Baohua, Wang, Yi, Hao, Quan, Gorbunova, Vera, Liu, Xinguang, Zhou, Zhongjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825207/
https://www.ncbi.nlm.nih.gov/pubmed/29474172
http://dx.doi.org/10.7554/eLife.32127
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author Ghosh, Shrestha
Wong, Sheung Kin
Jiang, Zhixin
Liu, Baohua
Wang, Yi
Hao, Quan
Gorbunova, Vera
Liu, Xinguang
Zhou, Zhongjun
author_facet Ghosh, Shrestha
Wong, Sheung Kin
Jiang, Zhixin
Liu, Baohua
Wang, Yi
Hao, Quan
Gorbunova, Vera
Liu, Xinguang
Zhou, Zhongjun
author_sort Ghosh, Shrestha
collection PubMed
description 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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spelling pubmed-58252072018-02-26 Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice Ghosh, Shrestha Wong, Sheung Kin Jiang, Zhixin Liu, Baohua Wang, Yi Hao, Quan Gorbunova, Vera Liu, Xinguang Zhou, Zhongjun eLife Biochemistry and Chemical Biology 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. eLife Sciences Publications, Ltd 2018-02-23 /pmc/articles/PMC5825207/ /pubmed/29474172 http://dx.doi.org/10.7554/eLife.32127 Text en © 2018, Ghosh et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Ghosh, Shrestha
Wong, Sheung Kin
Jiang, Zhixin
Liu, Baohua
Wang, Yi
Hao, Quan
Gorbunova, Vera
Liu, Xinguang
Zhou, Zhongjun
Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice
title Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice
title_full Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice
title_fullStr Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice
title_full_unstemmed Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice
title_short Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice
title_sort haploinsufficiency of trp53 dramatically extends the lifespan of sirt6-deficient mice
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825207/
https://www.ncbi.nlm.nih.gov/pubmed/29474172
http://dx.doi.org/10.7554/eLife.32127
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