SIRT1 Negatively Regulates the Activities, Functions, and Protein Levels of hMOF and TIP60

Peng, Lirong; Ling, Hongbo; Yuan, Zhigang; Fang, Bin; Bloom, Gregory; Fukasawa, Kenji; Koomen, John M.; Chen, Jiandong; Lane, William S.; Seto, Edward

doi:10.1128/mcb.00496-12

Cited by 84 publications

(93 citation statements)

References 91 publications

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“…Therefore, sirtuins may regulate multiple members of the NuA4 complex. In line with this observation, Peng et al previously described the SIRT1-regulated acetylation of the Esa1-like TIP60 and hMOF catalytic subunits in mammalian cells (39).…”

Section: Fig 4 Analysis Of Sites Targeted By Sirtuin Gcn5 and Esa1mentioning

confidence: 53%

Acetylome Profiling Reveals Overlap in the Regulation of Diverse Processes by Sirtuins, Gcn5, and Esa1

Downey

Johnson

Davey

et al. 2015

Molecular & Cellular Proteomics

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Although histone acetylation and deacetylation machineries (HATs and HDACs) regulate important aspects of cell function by targeting histone tails, recent work highlights that non-histone protein acetylation is also pervasive in eukaryotes. Here, we use quantitative mass-spectrometry to define acetylations targeted by the sirtuin family, previously implicated in the regulation of non-histone protein acetylation. To identify HATs that promote acetylation of these sites, we also performed this analysis in gcn5 (SAGA) and esa1 (NuA4) mutants. We observed strong sequence specificity for the sirtuins and for each of these HATs. Although the Gcn5 and Esa1 consensus sequences are entirely distinct, the sirtuin consensus overlaps almost entirely with that of Gcn5, suggesting a strong coordination between these two regulatory enzymes. Furthermore, by examining global acetylation in an ada2 mutant, which dissociates Gcn5 from the SAGA complex, we found that a subset of Gcn5 targets did not depend on an intact SAGA complex for targeting. Our work provides a framework for understanding how HAT and HDAC enzymes collaborate to regulate critical cellular processes related to growth and division. Molecular & Cellular

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Section: Fig 4 Analysis Of Sites Targeted By Sirtuin Gcn5 and Esa1mentioning

confidence: 53%

Acetylome Profiling Reveals Overlap in the Regulation of Diverse Processes by Sirtuins, Gcn5, and Esa1

Downey

Johnson

Davey

et al. 2015

Molecular & Cellular Proteomics

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show abstract

“…SIRT1 reduced the TIP60 half-life (Fig. 3D) (20), whereas HDAC3 increased the TIP60 half-life (Fig. 3B), and this stabilization is dominant over the effects of SIRT1 because cotransfection of both HDAC3 and SIRT1 with TIP60 resulted in an increase in the TIP60 half-life (Fig.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Histone Acetyltransferase TIP60 Function by Histone Deacetylase 3

Huang

Yang

et al. 2014

Journal of Biological Chemistry

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Background: TIP60 can be regulated by autoacetylation and deacetylated by SIRT1. Results: Novel lysine residues of TIP60 autoacetylation were identified, and TIP60 can be functionally regulated by HDAC3 through deacetylation. Conclusion: HDAC3 promotes TIP60 ubiquitination and cytoplasmic localization and protects cells from apoptosis after DNA damage. Significance: Our findings provide a better understanding of TIP60 regulatory mechanisms and its cellular functions.

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“…The high efficiency of Sirt1 in deacetylating MYST proteins such as MOF and Tip60 was also confirmed by several other recent studies. 91,151 Enzymatic analysis with the MOF deac and Tip60 deac showed that, in the deacetylated state, the cognate substrate acetylation activity of both enzymes decreased only slightly (e.g., The HAT enzyme activity was commonly characterized by using the isotope-labeled Ac-CoA. Due to the high sensitivity, the radioactive assay is suitable for kinetic and functional study of HATs.…”

Section: Discussionmentioning

confidence: 99%

“…Seto and coworkers obtained deacetylated MOF by treatment with Sirt1/NAD + . 91 Interestingly, their studies showed that the deacetylation of MOF reduces the cellular protein stability of MOF. 91 It is known that the MYST HATs frequently exist as multi-protein complexes.…”

Section: Chapter 4 Conclusion and Future Outlookmentioning

confidence: 99%

“…91 Interestingly, their studies showed that the deacetylation of MOF reduces the cellular protein stability of MOF. 91 It is known that the MYST HATs frequently exist as multi-protein complexes. 79,114,148,162 Presence of interactive proteins could provide biochemical cues regulating and altering the degree of MYST autoacetylation.…”

Section: Chapter 4 Conclusion and Future Outlookmentioning

confidence: 99%

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Histone Acetyltransferases

2005

Encyclopedic Reference of Genomics and Proteomics in Molecular Medicine

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As an important posttranslational modification, protein acetylation plays critical roles in many biological processes such as gene transcription, DNA damage repair, apoptosis and metabolism. The acetylation occurs on the ε-amino group of specific lysine residues, and is catalyzed by histone acetyltransferases (HATs). In cellular contexts, HATs are found to target hundreds and thousands of substrates including histone and nonhistone proteins. Lysine acetylation changes the microenvironment of protein and may potentially alter protein activity and protein-protein interaction. The goal of this dissertation project is to investigate the impact of lysine acetylation on the catalysis of MYST HATs, and to establish the strategy for labeling substrates of the MYST HATs at cellular level. To understand the regulatory mechanism of MYST HATs, a detailed study was carried out to investigate the active site lysine acetylation of two MYST HATs (MOF and Tip60). Autoradiography and immunoblotting data shows that mutation of active site lysine differentially affects the enzyme autoacetylation activity and the cognate substrate acetylation activity. In addition, deacetylated MOF and Tip60 were prepared by using the nonspecific lysine deacetylase Sirt1. Kinetic study demonstrated that the acetylation of the active site lysine on MYST HATs marginally modulates the HAT catalysis. This work provides new insights into the regulatory mechanism of MYST catalysis. In the second part of my work, we designed and synthesized a series of Ac-CoA analogs conjugated with alkynyl or azido functional groups. Meanwhile, the active site of the MOF was engineered to expand the cofactor binding capability. Fluorescence screening was carried out to characterize the enzyme activity to Ac-CoA analogs. MOF-I317A with all analogs and MOF-I317A/H273A-5HYCoA were identified and further applied in the labeling of the cognate histone H4 protein and HAT substrates in 293T cell lysate. Visualizing of the labeled substrate was achieved using the alkynyl or azido-tagged fluorescent reporters through the copper-catalyzed azide−alkyne cycloaddi on.As expected, the histone H4 protein was successfully labeled by the active enzyme-cofactor pairs. More intriguingly, multiple protein bands in cell lysate were labeled and observed. This work provides a new versatile strategy in exploring the substrates of MYST HATs at the proteomic level.

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SIRT1 Negatively Regulates the Activities, Functions, and Protein Levels of hMOF and TIP60

Cited by 84 publications

References 91 publications

Acetylome Profiling Reveals Overlap in the Regulation of Diverse Processes by Sirtuins, Gcn5, and Esa1

Acetylome Profiling Reveals Overlap in the Regulation of Diverse Processes by Sirtuins, Gcn5, and Esa1

Regulation of Histone Acetyltransferase TIP60 Function by Histone Deacetylase 3

Histone Acetyltransferases

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