Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism

Hubbard, Basil P.; Loh, Christine; Gomes, Ana P.; Li, Jun; Lu, Quinn; Doyle, Taylor Lg; Disch, Jeremy S.; Armour, Sean M.; Ellis, James L.; Vlasuk, George P.; Sinclair, David A.

doi:10.4161/cc.25268

Cited by 19 publications

(29 citation statements)

References 56 publications

(97 reference statements)

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“…By acetylating K112 and K215 on the N-terminal SirT1 binding domain of DBC1, hMOF disrupts DBC1-SirT1 interaction and increases the activity of SirT1. A recent study also independently identified four acetylation sites on DBC1, including the two sites found in our study (39). Interestingly, the DBC1 acetylation level is downregulated after DNA damage, possibly through ATM-dependent inhibition of DBC1-hMOF binding.…”

Section: Discussionmentioning

confidence: 66%

hMOF Acetylation of DBC1/CCAR2 Prevents Binding and Inhibition of SirT1

Zheng

Yang

Peng

et al. 2013

Molecular and Cellular Biology

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The NAD؉ -dependent deacetylase SirT1 regulates gene silencing and genomic stability in response to nutrient deprivation and DNA damage. An important regulator of SirT1 in mammalian cells is DBC1 (deleted in breast cancer 1; KIAA1967 or CCAR2), which binds to SirT1 and inhibits the deacetylation of substrates. Recent studies have revealed that ATM/ATR-mediated phosphorylation of DBC1 promotes binding to SirT1. Here we show that DBC1 is modified by acetylation on two N-terminal lysine residues (K112 and K215). The MYST family histone acetyltransferase hMOF (human MOF) is responsible for DBC1 acetylation. Acetylation of K112 and K215 inhibits DBC1-SirT1 binding and increases SirT1 deacetylase activity. SirT1 also promotes DBC1 deacetylation, suggesting the presence of a negative-feedback mechanism that stabilizes the SirT1-DBC1 complex and limits SirT1 activity. hMOF binding and acetylation of DBC1 are inhibited after DNA damage in an ATM-dependent fashion, contributing to increased SirT1-DBC1 binding after DNA damage. Furthermore, a DBC1 mutant that mimics the acetylated state fails to promote apoptosis after DNA damage. These results suggest that acetylation of DBC1 inhibits binding to SirT1 and serves as a mechanism that connects DNA damage signaling to SirT1 and cell fate determination.

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Section: Discussionmentioning

confidence: 66%

hMOF Acetylation of DBC1/CCAR2 Prevents Binding and Inhibition of SirT1

Zheng

Yang

Peng

et al. 2013

Molecular and Cellular Biology

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“…The outcome of this study has not been revealed in the context of a biological or pharmacodynamic effect in HD patients, but results are expected soon. Other therapeutic strategies to modulate SIRT1 activity include the inhibition of Dbc1-SIRT1 interaction, or the modulation of upstream modulators of SIRT1 modulating proteins, such as AROS or various enzymes associated with the regulation of NAD+ levels or SIRT1 activity via post-translational modifications (Hubbard et al 2013;Nin et al 2012;Raynes et al 2013;Zhao et al 2008). The controversy stems from the artifactual results of direct interaction between these small molecules and SIRT1 activation.…”

Section: Selective Modulators Of Lysine Deacetylasesmentioning

confidence: 99%

Behavioral Neurobiology of Huntington's Disease and Parkinson's Disease

Cenci¹,

Nguyen²

2015

Current Topics in Behavioral Neurosciences

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Current Topics in Behavioral Neurosciences provides critical and comprehensive discussions of the most significant areas of behavioral neuroscience research, written by leading international authorities. Each volume offers an informative and contemporary account of its subject, making it an unrivalled reference source. Titles in this series are available in both print and electronic formats.With the development of new methodologies for brain imaging, genetic and genomic analyses, molecular engineering of mutant animals, novel routes for drug delivery, and sophisticated cross-species behavioral assessments, it is now possible to study behavior relevant to psychiatric and neurological diseases and disorders on the physiological level. The Behavioral Neurosciences series focuses on ''translational medicine'' and cutting-edge technologies. Preclinical and clinical trials for the development of new diagnostics and therapeutics as well as prevention efforts are covered whenever possible.More information about this series at

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“…Proteins that contain homology to this domain typically have RNA binding capabilities, suggesting evolution from an ancient nucleic acid binding protein [ 16 ]. The NLS is an important site for regulation via post-translational modifications, where acetylation can disrupt DBC1 translocation into the nucleus and ultimately inhibit nuclear interactions [ 17 ]. The LZ is a structural motif that functions as a dimerization domain and can bind to DNA to regulate gene expression in DBC1, but it is likely non-functional in CCAR1 [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…The LZ is a structural motif that functions as a dimerization domain and can bind to DNA to regulate gene expression in DBC1, but it is likely non-functional in CCAR1 [ 18 ]. DBC1 interactions with epigenetic modifiers, nuclear receptors, and mRNA splicing components all take place within the N-terminal area [ 4 – 7 , 14 , 17 ]. The DBC1/SIRT1 interaction has been highly studied due to the important role that DBC1 plays in inhibiting the epigenetic modifications that are regulated by SIRT1.…”

Section: Introductionmentioning

confidence: 99%

“…The DBC1/SIRT1 interaction has been highly studied due to the important role that DBC1 plays in inhibiting the epigenetic modifications that are regulated by SIRT1. Conflicting data points to either the LZ of DBC1 (aa243–264) [ 4 , 14 , 19 , 20 ] or the N-terminal amino acids 1–240 as being critical for this interaction with SIRT1 [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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DBC1/CCAR2 and CCAR1 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor

Brunquell

Jia

Erwin

et al. 2014

BioMed Research International

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Deleted in breast cancer 1 (DBC1, CCAR2, KIAA1967) is a large, predominantly nuclear, multidomain protein that modulates gene expression by inhibiting several epigenetic modifiers, including the deacetylases SIRT1 and HDAC3, and the methyltransferase SUV39H1. DBC1 shares many highly conserved protein domains with its paralog cell cycle and apoptosis regulator 1 (CCAR1, CARP-1). In this study, we examined the full-length sequential and structural properties of DBC1 and CCAR1 from multiple species and correlated these properties with evolution. Our data shows that the conserved domains shared between DBC1 and CCAR1 have similar domain structures, as well as similar patterns of predicted disorder in less-conserved intrinsically disordered regions. Our analysis indicates similarities between DBC1, CCAR1, and the nematode protein lateral signaling target 3 (LST-3), suggesting that DBC1 and CCAR1 may have evolved from LST-3. Our data also suggests that DBC1 emerged later in evolution than CCAR1. DBC1 contains regions that show less conservation across species as compared to the same regions in CCAR1, suggesting a continuously evolving scenario for DBC1. Overall, this study provides insight into the structure and evolution of DBC1 and CCAR1, which may impact future studies on the biological functions of these proteins.

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Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism

Cited by 19 publications

References 56 publications

hMOF Acetylation of DBC1/CCAR2 Prevents Binding and Inhibition of SirT1

hMOF Acetylation of DBC1/CCAR2 Prevents Binding and Inhibition of SirT1

Behavioral Neurobiology of Huntington's Disease and Parkinson's Disease

DBC1/CCAR2 and CCAR1 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor

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