SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.

• Main Authors: Cian J Lynch, Zahid H Shah, Simon J Allison, Shafiq U Ahmed, Jack Ford, Lorna J Warnock, Han Li, Manuel Serrano, Jo Milner
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2010-10-01
• Series: PLoS ONE
• Online Access: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20975832/?tool=EBI

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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-ΔExon8 can regulate p53, while in reciprocal p53 can influence SIRT1 splice variation.<h4>Conclusions/significance</h4>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.