ArticleCell cycle (Georgetown, Tex.)2013
Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism.
Article in Cell cycle (Georgetown, Tex.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- Factors Determining Sirtuin-1 Target Engagement.Advanced biology · 2026Review
- Beyond deacetylation: crosstalk mechanisms and context-dependent regulation of sirtuin non-classical enzymatic functions in disease.Molecular medicine (Cambridge, Mass.) · 2026Review
- Inhibitory protein-protein interactions of the SIRT1 deacetylase are choreographed by post-translational modification.Protein science : a publication of the Protein Society · 2024Article
- Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat).Journal of enzyme inhibition and medicinal chemistry · 2020Article
- CCAR1 and CCAR2 as gene chameleons with antagonistic duality: Preclinical, human translational, and mechanistic basis.Cancer science · 2020Review
- SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases.Frontiers in pharmacology · 2020Review
- An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity.Molecular cell · 2018Article
- Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins.Nature communications · 2017Article
- Synthesis and Assay of SIRT1-Activating Compounds.Methods in enzymology · 2016Article
- Article
- CCAR2/DBC1 is required for Chk2-dependent KAP1 phosphorylation and repair of DNA damage.Oncotarget · 2015Article
- DBC1/CCAR2 and CCAR1 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor.BioMed research international · 2014Article
- hMOF acetylation of DBC1/CCAR2 prevents binding and inhibition of SirT1.Molecular and cellular biology · 2013Article
- Active regulator of SIRT1 is required for cancer cell survival but not for SIRT1 activity.Open biology · 2013Article
- A conserved acetylation switch enables pharmacological control of tubby-like protein stability.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SIRT1 is an NAD (+) -dependent deacetylase that counteracts multiple disease states associated with aging and may underlie some of the health benefits of calorie restriction. Understanding how SIRT1 is regulated in vivo could therefore lead to new strategies to treat age-related diseases. SIRT1 forms a stable complex with DBC1, an endogenous inhibitor. Little is known regarding the biochemical nature of SIRT1-DBC1 complex formation, how it is regulated and whether or not it is possible to block this interaction pharmacologically. In this study, we show that critical residues within the catalytic core of SIRT1 mediate binding to DBC1 via its N-terminal region, and that several carboxamide SIRT1 inhibitors, including EX-527, can completely block this interaction. We identify two acetylation sites on DBC1 that regulate its ability to bind SIRT1 and suppress its activity. Furthermore, we show that DBC1 itself is a substrate for SIRT1. Surprisingly, the effect of EX-527 on SIRT1-DBC1 binding is independent of DBC1 acetylation. Together, these data show that protein acetylation serves as an endogenous regulatory mechanism for SIRT1-DBC1 binding and illuminate a new path to developing small-molecule modulators of SIRT1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.