Journal Article

A single-nucleotide variation in a p53-binding site affects nutrient-sensitive human SIRT1 expression

Asma Naqvi, Timothy A. Hoffman, Jeremy DeRicco, Ajay Kumar, Cuk-Seong Kim, Saet-Byel Jung, Tohru Yamamori, Young-Rae Kim, Fardeen Mehdi, Santosh Kumar, Tuomo Rankinen, Eric Ravussin and Kaikobad Irani

in Human Molecular Genetics

Volume 19, issue 21, pages 4123-4133
Published in print November 2010 | ISSN: 0964-6906
Published online August 2010 | e-ISSN: 1460-2083 | DOI:
A single-nucleotide variation in a p53-binding site affects nutrient-sensitive human SIRT1 expression

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The SIRTUIN1 (SIRT1) deacetylase responds to changes in nutrient availability and regulates mammalian physiology and metabolism. Human and mouse SIRT1 are transcriptionally repressed by p53 via p53 response elements in their proximal promoters. Here, we identify a novel p53-binding sequence in the distal human SIRT1 promoter that is required for nutrient-sensitive SIRT1 transcription. In addition, we show that a common single-nucleotide (C/T) variation in this sequence affects nutrient deprivation-induced SIRT1 transcription, and calorie restriction-induced SIRT1 expression. The p53-binding sequence lies in a region of the SIRT1 promoter that also binds the transcriptional repressor Hypermethylated-In-Cancer-1 (HIC1). Nutrient deprivation increases occupancy by p53, while decreasing occupancy by HIC1, of this region of the promoter. HIC1 and p53 compete with each other for promoter occupancy. In comparison with the T variation, the C variation disrupts the mirror image symmetry of the p53-binding sequence, resulting in decreased binding to p53, decreased nutrient sensitivity of the promoter and impaired calorie restriction-stimulated tissue expression of SIRT1 and SIRT1 target genes AMPKα2 and PGC-1β. Thus, a common SNP in a novel p53-binding sequence in the human SIRT1 promoter affects nutrient-sensitive SIRT1 expression, and could have a significant impact on calorie restriction-induced, SIRT1-mediated, changes in human metabolism and physiology.

Journal Article.  6826 words.  Illustrated.

Subjects: Genetics and Genomics

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