SIRT1 Undergoes Alternative Splicing in a Novel Auto-Regulatory Loop with p53

Cian J. Lynch, Zahid H. Shah, Simon J. Allison, Shafiq U. Ahmed, Jack Ford, Lorna J. Warnock, Han Li, Manuel Serrano, Jo Milner

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36 Citations (Scopus)

Abstract

Background: 

The NAD-dependent deacetylase SIRT1 is a nutrient-sensitive coordinator of stress-tolerance, multiple homeostatic processes and healthspan, while p53 is a stress-responsive transcription factor and our paramount tumour suppressor. Thus, SIRT1-mediated inhibition of p53 has been identified as a key node in the common biology of cancer, metabolism, development and ageing. However, precisely how SIRT1 integrates such diverse processes remains to be elucidated. 

Methodology/Principal Findings: 

Here we report that SIRT1 is alternatively spliced in mammals, generating a novel SIRT1 isoform: SIRT1-ΔExon8. We show that SIRT1-ΔExon8 is expressed widely throughout normal human and mouse tissues, suggesting evolutionary conservation and critical function. Further studies demonstrate that the SIRT1-ΔExon8 isoform retains minimal deacetylase activity and exhibits distinct stress sensitivity, RNA/protein stability, and protein-protein interactions compared to classical SIRT1-Full-Length (SIRT1-FL). We also identify an auto-regulatory loop whereby SIRT1- DExon8 can regulate p53, while in reciprocal p53 can influence SIRT1 splice variation. 

Conclusions/Significance: 

We characterize the first alternative isoform of SIRT1 and demonstrate its evolutionary conservation in mammalian tissues. The results also reveal a new level of inter-dependency between p53 and SIRT1, two master regulators of multiple phenomena. Thus, previously-attributed SIRT1 functions may in fact be distributed between SIRT1 isoforms, with important implications for SIRT1 functional studies and the current search for SIRT1-activating therapeutics to combat age-related decline.

Original languageEnglish
Article numbere13502
Number of pages16
JournalPLoS One
Volume5
Issue number10
DOIs
Publication statusPublished - 21 Oct 2010
Externally publishedYes

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Lynch, C. J., Shah, Z. H., Allison, S. J., Ahmed, S. U., Ford, J., Warnock, L. J., ... Milner, J. (2010). SIRT1 Undergoes Alternative Splicing in a Novel Auto-Regulatory Loop with p53. PLoS One, 5(10), [e13502]. https://doi.org/10.1371/journal.pone.0013502