O‐GlcNAcase is essential for embryonic development and maintenance of genomic stability

Abstract

Summary Dysregulation of O‐GlcNAc modification catalyzed by O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) contributes to the etiology of chronic diseases of aging, including cancer, cardiovascular disease, type 2 diabetes, and Alzheimer’s disease. Here we found that natural aging in wild‐type mice was marked by a decrease in OGA and OGT protein levels and an increase in O‐GlcNAcylation in various tissues. Genetic disruption of OGA resulted in constitutively elevated O‐GlcNAcylation in embryos and led to neonatal lethality with developmental delay. Importantly, we observed that serum‐stimulated cell cycle entry induced increased O‐GlcNAcylation and decreased its level after release from G2/M arrest, indicating that O‐GlcNAc cycling by OGT and OGA is required for precise cell cycle control. Constitutively, elevated O‐GlcNAcylation by OGA disruption impaired cell proliferation and resulted in mitotic defects with downregulation of mitotic regulators. OGA loss led to mitotic defects including cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation. These findings suggest an important role for O‐GlcNAc cycling by OGA in embryonic development and the regulation of the maintenance of genomic stability linked to the aging process.

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

“…It was later demonstrated that inhibiting O-GlcNAcase with PUGNAc or reducing the expression of O-GlcNAcase (siRNA) increased the amount of APP O-GlcNAcylation and non-amyloidogenic α-secretase processing (Jacobsen and Iverfeldt 2011). This has further downstream effects such as increasing levels of the neuroprotective sAPPα fragment, which reduces Aβ secretion and suggests a protective role for O-GlcNAc (Kim et al 2012). Finally, treatment with the O-GlcNAcase inhibitor NButGT in a mouse model of AD resulted in reduced γ-secretase activity and subsequent attenuation of Aβ plaque production and inflammation in vivo, further highlighting the important protective role of O-GlcNAc under conditions of stress and neurodegeneration (Rissman et al 2007(Rissman et al , 2012.…”

“…Notably, in murine models deletion of OGT (Shafi et al 2000;O'Donnell et al 2004), EMeg32 (Boehmelt et al 2000b), or pgm3 ) leads to embryonic lethality, whereas deletion of O-GlcNAcase leads to perinatal lethality (Yang et al 2012). A number of hypomorphic alleles of pgm3 have been characterized, leading to cells and mice with different concentrations of UDP-GlcNAc ).…”

“…1). Highlighting the importance of O-GlcNAc in cellular homeostasis, deletion of OGT, OGlcNAcase, and other key enzymes in the hexosamine biosynthetic pathway (HBP) is lethal in mammals (Mio et al 1999;Greig et al 2007;Boehmelt et al 2000a, b;Shafi et al 2000;Forsythe et al 2006;Yang et al 2012).…”

O-Linked β-N-Acetylglucosaminylation (O-GlcNAcylation) in Primary and Metastatic Colorectal Cancer Clones and Effect of N-Acetyl-β-d-glucosaminidase Silencing on Cell Phenotype and Transcriptome

“…Moreover, increased UDP-GlcNAc slowed CRC cell growth and differentiation, O-GlcNAc reduction (by lowering UDP-GlcNAc) caused growth defects in fibroblasts, and galactosyltransferase injection or OGA inhibition resulted in damaged oocyte maturation (9). However, OGT overexpression in HeLa cells resulted in a polyploid phenotype with faulty cytokinesis, although its deletion was associated with delayed growth and increased death (9,32,40). In breast cancer cells, OGT silencing inhibited cell growth and decreased cell cycle progression (7).…”

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

“…Mounting evidence suggests that O-GlcNAc functions in the regulation of protein activity much like phosphorylation and other modifications. Although the molecular mechanisms remain mostly unresolved, O-GlcNAc has clear biological significance because deletion of the OGT or OGA gene in mice leads to embryonic lethality (23) or perinatal death (24), respectively. Furthermore, conditional deletion of OGT results in cellular senescence and apoptosis in numerous cell types, including T cells (25).…”