Negative Control of p53 by Sir2α Promotes Cell Survival under Stress
Open accessAbstract
The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha. These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.
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Analysis of p53 acetylation revealed that nicotinamide was effective in the assays.
“analysis of p53 acetylation, a known Sirtuin target40,41, revealed that nicotinamide was effective in our assays”
From Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining (2010) · cites this paper as [40]
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- Authors
- Luo, J., Nikolaev, A. Y., Imai, S.-I., Chen, D., Su, F., Shiloh, A., Guarente, L., & Gu, W.
- Affiliations
- Columbia University (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Gu, Wei
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2001-10
- Volume
- 107
- Issue
- 2
- Pages
- 137-148
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2012753961
- Cited by
- 2,081
- References
- 54
- Citations by year
- 2026: 21 · 2025: 35 · 2024: 30 · 2023: 37 · 2022: 54 · 2021: 71 · 2020: 62 · 2019: 62 · 2018: 71 · 2017: 84 · 2016: 97 · 2015: 105 · 2014: 134 · 2013: 127 · 2012: 121
- FWCI
- 39.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (2r01ca085533-16)
- National Cancer Institute (R01CA85533)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- p53, histone deacetylation, nicotinamide, p53 acetylation, apoptosis, DNA damage response, oxidative stress, stress response, cell survival, NAD+-dependent deacetylation, cancer therapy
- MeSH terms
- Animals, Cell Line, Cell Survival, DNA Damage, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Histone Deacetylases, Humans, NAD, Neoplasms, Niacinamide, Poly(ADP-ribose) Polymerases, Protein Binding, Blotting, Western, Transcriptional Activation, Trans-Activators, Polymerase Chain Reaction, Tumor Suppressor Protein p53, Mutagenesis, Site-Directed, Cell Death, Apoptosis, Point Mutation, Protein Structure, Tertiary, DNA, Complementary, Oxidative Stress, fas Receptor, Sirtuins, Mice, Sirtuin 1
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