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

<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...

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Autores principales:	Cian J Lynch, Zahid H Shah, Simon J Allison, Shafiq U Ahmed, Jack Ford, Lorna J Warnock, Han Li, Manuel Serrano, Jo Milner
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b83000647a4a4e2da18971e3da989111
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spelling	oai:doaj.org-article:b83000647a4a4e2da18971e3da9891112021-11-18T07:03:03ZSIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.1932-620310.1371/journal.pone.0013502https://doaj.org/article/b83000647a4a4e2da18971e3da9891112010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20975832/?tool=EBIhttps://doaj.org/toc/1932-6203<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.Cian J LynchZahid H ShahSimon J AllisonShafiq U AhmedJack FordLorna J WarnockHan LiManuel SerranoJo MilnerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10, p e13502 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cian J Lynch Zahid H Shah Simon J Allison Shafiq U Ahmed Jack Ford Lorna J Warnock Han Li Manuel Serrano Jo Milner SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.
description	<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.
format	article
author	Cian J Lynch Zahid H Shah Simon J Allison Shafiq U Ahmed Jack Ford Lorna J Warnock Han Li Manuel Serrano Jo Milner
author_facet	Cian J Lynch Zahid H Shah Simon J Allison Shafiq U Ahmed Jack Ford Lorna J Warnock Han Li Manuel Serrano Jo Milner
author_sort	Cian J Lynch
title	SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.
title_short	SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.
title_full	SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.
title_fullStr	SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.
title_full_unstemmed	SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.
title_sort	sirt1 undergoes alternative splicing in a novel auto-regulatory loop with p53.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/b83000647a4a4e2da18971e3da989111
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SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53.

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