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

Research output: Contribution to journalArticle

31 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.

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

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alternative splicing
Alternative Splicing
automobiles
Protein Isoforms
neoplasms
protein-protein interactions
stress tolerance
Conservation
transcription factors
RNA
mammals
Tissue
Biological Sciences
therapeutics
Proteins
Mammals
metabolism
Protein Stability
mice
RNA Stability

Cite this

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
Lynch, Cian J. ; Shah, Zahid H. ; Allison, Simon J. ; Ahmed, Shafiq U. ; Ford, Jack ; Warnock, Lorna J. ; Li, Han ; Serrano, Manuel ; Milner, Jo. / SIRT1 Undergoes Alternative Splicing in a Novel Auto-Regulatory Loop with p53. In: PLoS One. 2010 ; Vol. 5, No. 10.
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Lynch, CJ, Shah, ZH, Allison, SJ, Ahmed, SU, Ford, J, Warnock, LJ, Li, H, Serrano, M & Milner, J 2010, 'SIRT1 Undergoes Alternative Splicing in a Novel Auto-Regulatory Loop with p53', PLoS One, vol. 5, no. 10, e13502. https://doi.org/10.1371/journal.pone.0013502

SIRT1 Undergoes Alternative Splicing in a Novel Auto-Regulatory Loop with p53. / Lynch, Cian J.; Shah, Zahid H.; Allison, Simon J.; Ahmed, Shafiq U.; Ford, Jack; Warnock, Lorna J.; Li, Han; Serrano, Manuel; Milner, Jo.

In: PLoS One, Vol. 5, No. 10, e13502, 21.10.2010.

Research output: Contribution to journalArticle

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T1 - SIRT1 Undergoes Alternative Splicing in a Novel Auto-Regulatory Loop with p53

AU - Lynch, Cian J.

AU - Shah, Zahid H.

AU - Allison, Simon J.

AU - Ahmed, Shafiq U.

AU - Ford, Jack

AU - Warnock, Lorna J.

AU - Li, Han

AU - Serrano, Manuel

AU - Milner, Jo

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N2 - 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.

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