Journal article
SIRT1 deacetylates APE1 and regulates cellular base excision repair
Nucleic acids research, Vol.38(3), pp.832-845
01/2010
DOI: 10.1093/nar/gkp1039
PMCID: PMC2817463
PMID: 19934257
Abstract
Apurinic/apyrimidinic endonuclease-1 (APE1) is an essential enzyme in the base excision repair (BER) pathway. Here, we show that APE1 is a target of the SIRTUIN1 (SIRT1) protein deacetylase. SIRT1 associates with APE1, and this association is increased with genotoxic stress. SIRT1 deacetylates APE1
in vitro
and
in vivo
targeting lysines 6 and 7. Genotoxic insults stimulate lysine acetylation of APE1 which is antagonized by transcriptional upregulation of SIRT1. Knockdown of SIRT1 increases cellular abasic DNA content, sensitizing cells to death induced by genotoxic stress, and this vulnerability is rescued by overexpression of APE1. Activation of SIRT1 with resveratrol promotes binding of APE1 to the BER protein X-ray cross-complementing-1 (XRCC1), while inhibition of SIRT1 with nicotinamide (NAM) decreases this interaction. Genotoxic insult also increases binding of APE1 to XRCC1, and this increase is suppressed by NAM or knockdown of SIRT1. Finally, resveratrol increases APE activity in XRCC1-associated protein complexes, while NAM or knockdown of SIRT1 suppresses this DNA repair activity. These findings identify APE1 as a novel protein target of SIRT1, and suggest that SIRT1 plays a vital role in maintaining genomic integrity through regulation of the BER pathway.
Details
- Title: Subtitle
- SIRT1 deacetylates APE1 and regulates cellular base excision repair
- Creators
- Tohru Yamamori - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USAJeremy DeRicco - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USAAsma Naqvi - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USATimothy A Hoffman - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USAIlwola Mattagajasingh - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USAKenji Kasuno - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USASaet-Byel Jung - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USACuk-Seong Kim - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USAKaikobad Irani - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
- Resource Type
- Journal article
- Publication Details
- Nucleic acids research, Vol.38(3), pp.832-845
- Publisher
- Oxford University Press
- DOI
- 10.1093/nar/gkp1039
- PMID
- 19934257
- PMCID
- PMC2817463
- ISSN
- 0305-1048
- eISSN
- 1362-4962
- Language
- English
- Date published
- 01/2010
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984047729002771
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