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      Enzymatic and metabolic regulation of lysine succinylation


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          Lysine succinylation (Ksucc), defined as a transfer of a succinyl group to a lysine residue of a protein, is a newly identified protein post-translational modification 1–3. This chemical modification is reversible, dynamic, and evolutionarily conserved 4 where it has been comprehensively studied in both bacterial and mammalian cells 5–7. Numerous proteins involved in the regulation of various cellular and biological processes have been shown to be heavily succinylated 5–7. Emerging clinical data provides evidence that dysregulation of Ksucc is correlated with the development of several diseases, including cardiovascular diseases and cancer 7–9. Therefore, an in-depth understanding of Ksucc and its regulation is important not only for understanding its physiological function but also for developing drug therapies and targeted agents for these diseases. In this review, we highlight some of the recent advances in understanding the role of Ksucc and desuccinylation under physiological and pathological conditions.

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          Most cited references21

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          Sirtuins in mammals: insights into their biological function.

          Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.
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            Proteomic analysis of post-translational modifications.

            Post-translational modifications modulate the activity of most eukaryote proteins. Analysis of these modifications presents formidable challenges but their determination generates indispensable insight into biological function. Strategies developed to characterize individual proteins are now systematically applied to protein populations. The combination of function- or structure-based purification of modified 'subproteomes', such as phosphorylated proteins or modified membrane proteins, with mass spectrometry is proving particularly successful. To map modification sites in molecular detail, novel mass spectrometric peptide sequencing and analysis technologies hold tremendous potential. Finally, stable isotope labeling strategies in combination with mass spectrometry have been applied successfully to study the dynamics of modifications.
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              The diverse functions of Dot1 and H3K79 methylation.

              DOT1 (disruptor of telomeric silencing; also called Kmt4) was initially discovered in budding yeast in a genetic screen for genes whose deletion confers defects in telomeric silencing. Since the discovery ∼10 years ago that Dot1 and its mammalian homolog, DOT1L (DOT1-Like), possess histone methyltransferase activity toward histone H3 Lys 79, great progress has been made in characterizing their enzymatic activities and the role of Dot1/DOT1L-mediated H3K79 methylation in transcriptional regulation, cell cycle regulation, and the DNA damage response. In addition, gene disruption in mice has revealed that mouse DOT1L plays an essential role in embryonic development, hematopoiesis, cardiac function, and the development of leukemia. The involvement of DOT1L enzymatic activity in leukemogenesis driven by a subset of MLL (mixed-lineage leukemia) fusion proteins raises the possibility of targeting DOT1L for therapeutic intervention.

                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                08 October 2019
                June 2020
                08 October 2019
                : 7
                : 2
                : 166-171
                [a ]Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
                [b ]Division of Oncology Research, Mayo Clinic, Rochester, MN, USA
                Author notes
                []Corresponding author. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. Hitosugi.Taro@ 123456mayo.edu
                © 2019 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 28 February 2019
                : 11 September 2019
                : 27 September 2019

                lysine succinylation,metabolism,post-translational modification,sirt5,succinyl-coa


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