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293T cell mitotic AP-MS anti-SIRT6-FLAG 201113

ABSTRACT: The study found reciprocal regulation between SIRT6 and APC/C. While SIRT6 is ubiquitinated by APC/C and degraded, CDH1, a co-activator of APC/C, is also deacetylated by SIRT6 and degraded.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Kidney

DISEASE(S): Acute Leukemia

SUBMITTER: Helin Wang

LAB HEAD: Haiteng Deng

PROVIDER: PXD022500 | Pride | 2021-09-09

REPOSITORIES: Pride

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Reciprocal interaction between SIRT6 and APC/C regulates genomic stability.

Wang Helin H Feng Kangze K Wang Qingtao Q Deng Haiteng H

Scientific reports 20210709 1

SIRT6 is an NAD<sup>+</sup>-dependent deacetylase that plays an important role in mitosis fidelity and genome stability. In the present study, we found that SIRT6 overexpression leads to mitosis defects and aneuploidy. We identified SIRT6 as a novel substrate of anaphase-promoting complex/cyclosome (APC/C), which is a master regulator of mitosis. Both CDH1 and CDC20, co-activators of APC/C, mediated SIRT6 degradation via the ubiquitination-proteasome pathway. Reciprocally, SIRT6 also deacetylate ...[more]

PMID: 34244565

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WT/SIRT6 KO 293T cell AP-MS anti-CDH1-HA

Project description:The study found reciprocal regulation between SIRT6 and APC/C. While SIRT6 is ubiquitinated by APC/C and degraded, CDH1, a co-activator of APC/C, is also deacetylated by SIRT6 and degraded.

2021-09-09 | PXD022402 | Pride

The effect of sirtuin 6 overexpression on TNFa stimulation.

Project description:SIRT6 has been implicated in a range of biological processes including inflammation, aging and the control of metabolism. Hence inhibitors or activators of SIRT6 have the potential to be therapeutics for a number of indications. Genome wide expression studies were used to investigate the effect of overexpression of SIRT6 and mutant SIRT6 on a wide range of NFκB dependent gene expression HEK293 cells were transfected with expression vectors encoding wild type SIRT6 or the H133W mutant followed by stimulation with TNFα for one hour.

2011-07-30 | E-GEOD-28548 | biostudies-arrayexpress

SIRT6 suppresses pancreatic cancer through control of Lin28b [ChIP-seq]

Project description:Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1 and IGF2BP3. This epigenetic program defines a distinct subset representing 30-40% of human PDAC, characterized by poor prognosis and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor, and uncover the Lin28b pathway as a potential therapeutic target in a molecularlydefined PDAC subset. ChIP-Seq experiments to examine H3K56ac histone modifications in murine PDAC cells that are Sirt6 wild type (WT), Sirt6 knock-out (KO), and Sirt6 KO cells engineered to express Sirt6 WT (Sirt6 KO + Sirt6 WT Restored).

2016-04-01 | E-GEOD-79503 | biostudies-arrayexpress

SIRT6 regulates redox homeostasis in human mesenchymal stem cells by the transactivation of NRF2

Project description:We investigated the effect of SIRT6-knockout on gene expression and H3K4me3 modification profile in human mesenchymal stem cells. RNAs isolated from SIRT6+/+ and SIRT6-/- hMSCs at early and late passages were sequenced, respectively. And, H3K4me3 ChIP-seq was performed upon the SIRT6 deleted hMSC and WT at early stage, respectively.

2016-01-04 | E-GEOD-64642 | biostudies-arrayexpress

SIRT6 and SIRT7 binding proteome

Project description:To find the SIRT6 and SIRT7 binding proteins, we expressed V5-tagged SIRT6 and SIRT7 and pulled down this protein with anti-V5 agarose affinity gel. Sirtuins are a family of NAD-dependent deacetylases which deacetylate not only histones but also a wide range of target proteins. Sirtuins are conserved from yeast to mammal, and are known to regulate many processes such as cellular metabolism, apoptosis, cellular senescence, cell cycle, and organism-level aging. Among the members of sirtuins showing different subcellular localization, SIRT1, SIRT6 and SIRT7 are localized in nucleus. Whereas many functions and interacting proteins of SIRT1 have been studied, functions of SIRT6 and SIRT7 are not extensively revealed yet. Since it is important to understand the molecular function of SIRT6 and SIRT7, we here aimed to identify interacting proteins in mammalian cells.<br>Extra primary submitter: <a href="mailto:nglee@postech.ac.kr" target="_top">Namgyu Lee</a>, Department of Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea<br>Lab head: <a href="mailto:kchoi@postech.ac.kr" target="_top">Kwan Yong Choi</a>, Department of Life Sciences and Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 790-784, Republ ic of Korea

2014-04-28 | PXD000159 | Pride

A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A

Project description:Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in the regulation of aging and metabolism. Targeted sequencing identified a SIRT6 allele containing two linked substitutions (N308K/A313S) as enriched in Ashkenazi Jewish (AJ) centenarians as compared to AJ control individuals. Characterization of this SIRT6 (centSIRT6) allele demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double strand break repair, and more robust cancer cell killing compared to the wild type. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

2022-10-21 | PXD035689 | Pride

Sirt6 in Hepatocytes

Project description:The aim of our study was to identify differentially regulated genes specifically in hepatocytes (versus in total liver extracts) when Sirt6 is deleted.

2015-01-10 | E-MTAB-1477 | biostudies-arrayexpress

Silencing of pericentric heterochromatin associated with SIRT6-dependent H3K18 deacetylation protects against mitotic errors and cellular senescence

Project description:Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing is observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover a pivotal role of the human SIRT6 enzyme in pericentric transcriptional silencing, and this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, histone H3 lysine K18 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, RNAi-depletion of these transcripts rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and H3K18Ac regulation at heterochromatin, and demonstrate the pathogenic role of de-regulated pericentric transcription in aging- and cancer- related cellular dysfunction. H3K18ac, H3K9ac, H3K9me3, H3K56ac and Input ChIP-seq for U2OS cell

2016-04-04 | E-GEOD-69809 | biostudies-arrayexpress

SIRT6 regulates glucose metabolism and glutamatergic synapse in the mouse retina

Project description:Microarray analysis on total retinal RNA from 15 day old Sirt6 wild-type (WT) and knock-out (KO) mice. The retina is one of the major energy consuming tissues within the body. In this context, synaptic transmission between light-excited rod photoreceptors and downstream ON-bipolar neurons is a highly demanding energy consuming process. Sirtuin 6 (SIRT6), a NAD-dependent deacylase, plays a key role in regulating glucose metabolism. In this study, we demonstrate that SIRT6 is highly expressed in the retina, controlling levels of histone H3K9 and H3K56 acetylation. Notably, despite apparent normal histology, SIRT6 deficiency caused major retinal transmission defects concomitant to changes in expression of glycolytic genes and glutamate receptors, as well as elevated levels of apoptosis in inner retina cells. Our results identify SIRT6 as a critical modulator of retinal function, likely through its effects on chromatin. Microarray analysis of total retinal RNA from 15 day old Sirt6 wild-type (WT) and knock-out (KO) mice with 3 replicates in each condition using the Affymetrix Mouse Gene 2.1 ST array (transcript (gene) version).

2014-07-30 | E-GEOD-56563 | biostudies-arrayexpress

SIRT6 and SIRT1 contribute to circadian gene expression

Project description:Comparison of the hepatic circadian transcriptomes reveals that SIRT6 and SIRT1 separately control transcriptional specificity, and therefore, define distinctly partitioned classes of circadian genes. Livers from WT and SIRT6 KO mice, and livers from WT and SIRT1 KO mice, were harvested over the circadian cycle at ZT 0, 4, 8, 12, 16 and 20 for gene expression analysis.

2014-08-05 | E-GEOD-57830 | biostudies-arrayexpress

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