OGT and OGA: Sweet guardians of the genome

The past 4 decades have witnessed tremendous efforts in deciphering the role of O-GlcNAcylation in a plethora of biological processes. Chemists and biologists have joined hand in hand in the sweet adventure to unravel this unique and universal yet uncharted post-translational modification, and the recent advent of cutting-edge chemical biology and mass spectrometry tools has greatly facilitated the process. Compared with O-GlcNAc, DNA damage response (DDR) is a relatively intensively studied area that could be traced to before the elucidation of the structure of DNA. Unexpectedly, yet somewhat expectedly, O-GlcNAc has been found to regulate various DDR pathways: homologous recombination, nonhomologous end joining, base excision repair, and translesion DNA synthesis. In this review, we first cover the recent structural studies of the O-GlcNAc transferase and O-GlcNAcase, the elegant duo that “writes” and “erases” O-GlcNAc modification. Then we delineate the intricate roles of O-GlcNAc transferase and O-GlcNAcase in DDR. We envision that this is only the beginning of our full appreciation of how O-GlcNAc regulates the blueprint of life—DNA. The past 4 decades have witnessed tremendous efforts in deciphering the role of O-GlcNAcylation in a plethora of biological processes. Chemists and biologists have joined hand in hand in the sweet adventure to unravel this unique and universal yet uncharted post-translational modification, and the recent advent of cutting-edge chemical biology and mass spectrometry tools has greatly facilitated the process. Compared with O-GlcNAc, DNA damage response (DDR) is a relatively intensively studied area that could be traced to before the elucidation of the structure of DNA. Unexpectedly, yet somewhat expectedly, O-GlcNAc has been found to regulate various DDR pathways: homologous recombination, nonhomologous end joining, base excision repair, and translesion DNA synthesis. In this review, we first cover the recent structural studies of the O-GlcNAc transferase and O-GlcNAcase, the elegant duo that “writes” and “erases” O-GlcNAc modification. Then we delineate the intricate roles of O-GlcNAc transferase and O-GlcNAcase in DDR. We envision that this is only the beginning of our full appreciation of how O-GlcNAc regulates the blueprint of life—DNA. O-GlcNAcylation, the quintessential glycosylation that occurs intracellularly, is catalyzed by the sole O-GlcNAc transferase (OGT) and removed by the only glycosidase O-GlcNAcase (OGA). Discovered exactly 4 decades ago, O-GlcNAcylation mediates various cellular processes, including transcription, translation, autophagy, and immune response (1Hart G.W. Slawson C. Ramirez-Correa G. Lagerlof O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease.Annu. Rev. Biochem. 2011; 80: 825-858Crossref PubMed Scopus (1000) Google Scholar, 2Yang X. Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions.Nat. Rev. Mol. Cell Biol. 2017; 18: 452-465Crossref PubMed Scopus (700) Google Scholar). Its aberrancy leads to many human diseases, such as cancer, cardiovascular diseases, and neurodegenerative diseases. Mechanistically, O-GlcNAcylation frequently crosstalks with other post-translational modifications (PTMs), such as phosphorylation, acetylation, ubiquitination, and recently poly(ADP-ribosyl)ation (PARylation), either by regulating the “writer” or “eraser” enzymes or by directly competing for the same amino acids on the substrate proteins. One of the most frequently studied examples is the crosstalk between O-GlcNAcylation and phosphorylation. Ser residues or Thr residues on the same protein may be modified by either O-GlcNAcylation or phosphorylation, creating the potential for competition at the same or proximal sites. During the cell cycle, cells are exposed to various internal and external hazards. Internal DNA damage primarily occurs because of hydrolysis and oxidation of chemically active DNA by water and intracellular reactive oxygen species (ROS). External DNA damage, on the other hand, is caused by environmental, physical, and chemical agents such as UV and ionizing radiation (IR), alkylating agents, and crosslinking agents. These hazardous factors lead to different types of DNA damage, including abasic sites, mismatches, interstrand crosslinks (ICLs), single-strand breaks (SSBs), and double-stranded breaks (DSBs) (3Carusillo A. Mussolino C. DNA damage: from threat to treatment.Cells. 2020; 9: 1665Crossref PubMed Scopus (101) Google Scholar). Among these lesions, DSBs are particularly harmful and pose a significant threat to cells. To counteract these damages, cells have evolved DNA damage response (DDR) pathways that identify and repair specific types of DNA lesion, ensuring the integrity of the genome. Dysregulation of DDR results in chromosome instability and eventually lead to tumorigenesis (4Li J. Sun H. Huang Y. Wang Y. Liu Y. Chen X. Pathways and assays for DNA double-strand break repair by homologous recombination.Acta Biochim. Biophys. Sin. (Shanghai). 2019; 51: 879-889Crossref PubMed Scopus (43) Google Scholar). The DDR pathways include homologous recombination (HR), nonhomologous end-joining (NHEJ), mismatch repair, base excision repair (BER), nucleotide excision repair, and ICL repair (5Chatterjee N. Walker G.C. Mechanisms of DNA damage, repair, and mutagenesis.Environ. Mol. Mutagen. 2017; 58: 235-263Crossref PubMed Scopus (1070) Google Scholar, 6Stewart R.A. Pilie P.G. Yap T.A. Development of PARP and immune-checkpoint inhibitor combinations.Cancer Res. 2018; 78: 6717-6725Crossref PubMed Scopus (149) Google Scholar). These repair processes are crucial for maintaining genome stability (7Colombo C.V. Gnugnoli M. Gobbini E. Longhese M.P. How do cells sense DNA lesions?.Biochem. Soc. Trans. 2020; 48: 677-691Crossref PubMed Scopus (12) Google Scholar). Recent years, emerging evidence has implicated O-GlcNAcylation in DDR. Here, we first review the recent structural insights of OGT and OGA, as scientists strive to answer why there is only one enzyme for both writing and erasing O-GlcNAc. The advent of cryo-EM surely brought new insights into the question but still left many issues unanswered. Then we provide a comprehensive review of the current understanding of the role of O-GlcNAcylation in DDR, highlighting its impact on DNA replication, DNA repair pathways, and genome integrity. OGT is responsible for catalyzing the transfer of O-GlcNAc from cellular UDP-GlcNAc onto Ser residues or Thr residues of a myriad of cytoplasmic and nuclear proteins, forming β-linked O-GlcNAc additions (8Torres C.R. Hart G.W. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc.J. Biol. Chem. 1984; 259: 3308-3317Abstract Full Text PubMed Google Scholar, Hart G.W. of O-GlcNAc to nuclear and cytoplasmic proteins. of a Biol. Chem. Full Text PubMed Google is responsible for J. M. or of O-GlcNAc Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar). the of have of that O-GlcNAc modification, to efforts to how OGT its OGT that its and Hart G.W. glycosylation of nuclear and proteins. and of a unique O-GlcNAc transferase with Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar, Hart G.W. of a and nuclear O-GlcNAc of the Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar, M. transferase is a protein Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar). and unique to the there is between and is in the J. Walker The of a sweet structure and of O-GlcNAc Biol. Chem. 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