SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.
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Lynch CJ, Shah ZH, Allison SJ, Ahmed SU, Ford J, Warnock LJ, Li H, Serrano M, Milner J
SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.
PLoS One. 2010 Oct 21;5(10):e13502. doi: 10.1371/journal.pone.0013502.
- PubMed ID
- 20975832 [ View in PubMed]
- 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-DeltaExon8. We show that SIRT1-DeltaExon8 is expressed widely throughout normal human and mouse tissues, suggesting evolutionary conservation and critical function. Further studies demonstrate that the SIRT1-DeltaExon8 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-DeltaExon8 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.