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

Summary Dysregulation of O-GlcNAc modification catalyzed by O-GlcNActransferase(OGT)andO-GlcNAcase(OGA)contributestotheetiol-ogy of chronic diseases of aging, including cancer, cardiovasculardisease, type 2 diabetes, and Alzheimer’s disease. Here we foundthat natural aging in wild-type mice was marked by a decrease inOGAand OGT proteinlevels and an increasein O-GlcNAcylation invarious tissues. Genetic disruption of OGA resulted in constitu-tively elevated O-GlcNAcylation in embryos and led to neonatallethality with developmental delay. Importantly, we observedthat serum-stimulated cell cycle entry induced increased O-GlcNA-cylation and decreased its level after release from G2⁄M arrest,indicating that O-GlcNAc cycling by OGT and OGA is required forprecise cell cycle control. Constitutively, elevatedO-GlcNAcylationby OGA disruption impaired cell proliferation and resulted inmitotic defects with downregulation of mitotic regulators. OGAloss led to mitotic defects including cytokinesis failure andbinucleation, increased lagging chromosomes, and micronucleiformation. These findings suggest an important role for O-GlcNAccycling by OGA in embryonic development and the regulation ofthemaintenanceofgenomicstabilitylinkedtotheagingprocess.Key words: aging; genomic instability; O-GlcNAcase;O-GlcNAcylation; O-GlcNAc transferase.