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      O-GlcNAc: A Sweetheart of the Cell Cycle and DNA Damage Response

      review-article
      , *
      Frontiers in Endocrinology
      Frontiers Media S.A.
      O-GlcNAc, mitosis, replication, cytokinesis, DNA damage response

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          Abstract

          The addition and removal of O-linked N-acetylglucosamine (O-GlcNAc) to and from the Ser and Thr residues of proteins is an emerging post-translational modification. Unlike phosphorylation, which requires a legion of kinases and phosphatases, O-GlcNAc is catalyzed by the sole enzyme in mammals, O-GlcNAc transferase (OGT), and reversed by the sole enzyme, O-GlcNAcase (OGA). With the advent of new technologies, identification of O-GlcNAcylated proteins, followed by pinpointing the modified residues and understanding the underlying molecular function of the modification has become the very heart of the O-GlcNAc biology. O-GlcNAc plays a multifaceted role during the unperturbed cell cycle, including regulating DNA replication, mitosis, and cytokinesis. When the cell cycle is challenged by DNA damage stresses, O-GlcNAc also protects genome integrity via modifying an array of histones, kinases as well as scaffold proteins. Here we will focus on both cell cycle progression and the DNA damage response, summarize what we have learned about the role of O-GlcNAc in these processes and envision a sweeter research future.

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          Most cited references89

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          The DNA damage response: ten years after.

          The DNA damage response (DDR), through the action of sensors, transducers, and effectors, orchestrates the appropriate repair of DNA damage and resolution of DNA replication problems, coordinating these processes with ongoing cellular physiology. In the past decade, we have witnessed an explosion in understanding of DNA damage sensing, signaling, and the complex interplay between protein phosphorylation and the ubiquitin pathway employed by the DDR network to execute the response to DNA damage. These findings have important implications for aging and cancer.
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            Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease.

            O-GlcNAcylation is the addition of β-D-N-acetylglucosamine to serine or threonine residues of nuclear and cytoplasmic proteins. O-linked N-acetylglucosamine (O-GlcNAc) was not discovered until the early 1980s and still remains difficult to detect and quantify. Nonetheless, O-GlcNAc is highly abundant and cycles on proteins with a timescale similar to protein phosphorylation. O-GlcNAc occurs in organisms ranging from some bacteria to protozoans and metazoans, including plants and nematodes up the evolutionary tree to man. O-GlcNAcylation is mostly on nuclear proteins, but it occurs in all intracellular compartments, including mitochondria. Recent glycomic analyses have shown that O-GlcNAcylation has surprisingly extensive cross talk with phosphorylation, where it serves as a nutrient/stress sensor to modulate signaling, transcription, and cytoskeletal functions. Abnormal amounts of O-GlcNAcylation underlie the etiology of insulin resistance and glucose toxicity in diabetes, and this type of modification plays a direct role in neurodegenerative disease. Many oncogenic proteins and tumor suppressor proteins are also regulated by O-GlcNAcylation. Current data justify extensive efforts toward a better understanding of this invisible, yet abundant, modification. As tools for the study of O-GlcNAc become more facile and available, exponential growth in this area of research will eventually take place.
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              Peptide and protein sequence analysis by electron transfer dissociation mass spectrometry.

              Peptide sequence analysis using a combination of gas-phase ion/ion chemistry and tandem mass spectrometry (MS/MS) is demonstrated. Singly charged anthracene anions transfer an electron to multiply protonated peptides in a radio frequency quadrupole linear ion trap (QLT) and induce fragmentation of the peptide backbone along pathways that are analogous to those observed in electron capture dissociation. Modifications to the QLT that enable this ion/ion chemistry are presented, and automated acquisition of high-quality, single-scan electron transfer dissociation MS/MS spectra of phosphopeptides separated by nanoflow HPLC is described.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                30 July 2018
                2018
                : 9
                : 415
                Affiliations
                Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University , Beijing, China
                Author notes

                Edited by: Tony Lefebvre, Lille University of Science and Technology, France

                Reviewed by: Anne-Sophie Edouart, Centre National de la Recherche Scientifique (CNRS), France; Hai-Bin Ruan, University of Minnesota Twin Cities, United States; Chad Slawson, Kansas University of Medical Center Research Institute, United States

                *Correspondence: Jing Li jing_li@ 123456mail.cnu.edu.cn

                This article was submitted to Molecular and Structural Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2018.00415
                6077185
                30105004
                40052c08-ade4-4b91-aad4-a75e636ed651
                Copyright © 2018 Liu and Li.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 April 2018
                : 02 July 2018
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 107, Pages: 11, Words: 9600
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                o-glcnac,mitosis,replication,cytokinesis,dna damage response
                Endocrinology & Diabetes
                o-glcnac, mitosis, replication, cytokinesis, dna damage response

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