SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability

Li, Lei; Shi, Lan Bo; Yang, Shangda; Yan, Ruorong; Zhang, Di; Yang, Jianguo; He, Lin; Li, Wanjin; Yi, Xin; Sun, Luyang; Liang, Jing; Cheng, Zhongyi; Shi, Lei; Shang, Yongfeng; Yu, Wenhua

doi:10.1038/ncomms12235

Cited by 289 publications

(305 citation statements)

References 69 publications

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“…γH2AX is an important marker for DNA damage response. In previous publication (Li et al, 2016), the authors observed different DNA damage response in different cell lines. In MCF7 cells, depletion of SIRT7 significantly enhanced γH2AX level.…”

Section: Discussionmentioning

confidence: 91%

“…Furthermore, SIRT7 is also shown to be an activator that stimulates ribosomal biogenesis in dividing cells (Tsai et al, 2014) by activating rDNA transcription through multiple mechanisms (Chen et al, 2016; Ford et al, 2006; Tsai et al, 2012), thereby supporting the high biosynthetic and metabolic demands of cancer cells. Recent studies also show that SIRT7 can modulate DNA repair and maintain genome integrity (Li et al, 2016; Vazquez et al, 2016). In addition to its role in cancer, SIRT7 also plays an important role in the regulation of cell death and damage by inhibiting p53, Ras, and Akt signaling pathways in the heart (Vakhrusheva et al, 2008a; Vakhrusheva et al, 2008b).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Serine-Threonine Kinase Akt Activation by NAD + -Dependent Deacetylase SIRT7

Qin

et al. 2017

Cell Reports

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SUMMARY The Akt pathway is a central regulator that promotes cell survival in response to extracellular signals. Depletion of SIRT7, a NAD+-dependent deacetylase which is the least studied sirtuin, is known to significantly increase Akt activity in mice through unknown mechanisms. In this study, we demonstrate that SIRT7 depletion in breast cancer cells results in Akt hyper-phosphorylation and increases cell survival following genotoxic stress. Mechanistically, SIRT7 specifically interacts with and deacetylates FKBP51 at residue Lysines 28 and 155 (K28 and K155), resulting in enhanced interactions among FKBP51/Akt/PHLPP, and Akt dephosphorylation. Mutating both lysines to arginines abolishes the effect of SIRT7 on Akt activity through FKBP51 deacetylation. Finally, energy stress strengthens SIRT7 mediated effects on Akt dephosphorylation through FKBP51, thus, sensitizes cancer cells to cytotoxic agents. These results reveal a direct role of SIRT7 in Akt regulation and raise the possibility of using the glucose analog 2-Deoxy-D-glucose (2DG) as a chemo-sensitizing agent.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Regulation of Serine-Threonine Kinase Akt Activation by NAD + -Dependent Deacetylase SIRT7

Qin

et al. 2017

Cell Reports

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“…The recent identification of a direct role for SIRT7 in the DSB repair of the NHEJ pathway established a functional link between SIRT7-mediated H3K18 deacetylation and 53BP1 recruitment to sites of DNA damage 26. Interestingly, SIRT7 overexpression increased both NHEJ and HR repair efficiency in reporter cell lines 17, 22. Although we did not determine whether SIRT7 affects the NHEJ or HR repair pathways, we provide clear evidence that 5-FU induced SIRT7 degradation is involved in increased radiosensitivity in colorectal cancer cell lines and immune-compromised mice.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer

Tang¹,

Lu²,

Zhang³

et al. 2017

Theranostics

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5-Fluorouracil (5-FU) combined with radiotherapy is a common treatment strategy to treat human cancers, but the underlying mechanisms of this combination treatment remain unclear. Here, we report that NAD+-dependent deacetylase sirtuin-7 (SIRT7) protein levels were decreased due to 5-FU exposure rendering colorectal cancer cells sensitive to radiation. We found that SIRT7 downregulation was mediated via a Tat-binding Protein 1 (TBP1) proteasome-dependent pathway. Specifically, TBP1 was dephosphorylated at tyrosine 381 upon 5-FU treatment, which enhanced its direct interaction with SIRT7 and targeted it for degradation. Depletion of SIRT7 in cultured colorectal cancer cells induced radiosensitivity triggering cell death. Interestingly, decreased levels of SIRT7 mediated by 5-FU correlated well with improved therapeutic effect in patients with rectal cancer and with inhibited tumor growth in immune-compromised mice post-irradiation. Taken together, these data suggest that 5-FU induces radiosensitivity via SIRT7 degradation to favor a cell death pathway in targeted cancer cells. Thus, downregulation of SIRT7 could be a promising pharmacologic strategy to increase the effectiveness of chemoradiation therapy in cancer patients.

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“…In these assay conditions, SIRT7 did not exhibit any measurable activity, likely due to its preference for nucleosomal histones over peptide substrates 50 . Using cell-based proteomics methods, SIRT7 was characterized as a histone desuccinylase with function in the DNA damage response 51 . Another study demonstrated that SIRT3 has decrotonylase activity in vitro and that knockdown of SIRT3 increased histone Kcr levels, which correlated with increases in gene expression 52 .…”

Section: Writers and Erasers Of Lys Acylationmentioning

confidence: 99%

Metabolic regulation of gene expression through histone acylations

Sabari

Zhang

Allis

et al. 2016

Nat Rev Mol Cell Biol

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775

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Eight types of short-chain lysine (Lys) acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. Emerging evidence suggest that these histone modifications affect gene expression and are structurally and functionally different from the widely studied histone Lys acetylation. In this review, we discuss the regulation of non-acetyl histone acylation by enzymatic and metabolic mechanisms, acylation “reader” proteins that mediate the effects of different acylations, and their physiological functions, including in signal-dependent gene activation, spermatogenesis, tissue injury and metabolic-induced stress. We propose a model to explain our present understanding of how differential histone acylation is regulated by metabolism of the different acyl-CoA forms, which in turn modulate the regulation of gene expression.

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SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability

Cited by 289 publications

References 69 publications

Regulation of Serine-Threonine Kinase Akt Activation by NAD + -Dependent Deacetylase SIRT7

Regulation of Serine-Threonine Kinase Akt Activation by NAD + -Dependent Deacetylase SIRT7

Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer

Metabolic regulation of gene expression through histone acylations

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