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

Abstract

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.

• Authors: Yong Ryoul Yang, Minseok Song, Ho Lee, Yoon Jeon, Eun-Jeong Choi, Hyun-Jun Jang, Hyo Youl Moon, Ha-Young Byun, Eung-Kyun Kim, Dae Hyun Kim, Mi Nam Lee, Ara Koh, Jaewang Ghim, Jang Hyun Choi, Whaseon Lee-Kwon, Kyong Tai Kim, Sung Ho Ryu, Pann-Ghill Suh
• Journal: Aging cell (Aging Cell) Vol. 11 Issue 3 Pg. 439-48 (Jun 2012) ISSN: 1474-9726 [Electronic] England
• PMID: 22314054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Chemical References

• N-Acetylglucosaminyltransferases
• O-GlcNAc transferase

Topics

• Age Factors
• Animals
• Cell Line
• Embryonic Development (genetics)
• Female
• Genomic Instability
• Male
• Mice
• Mice, Knockout
• N-Acetylglucosaminyltransferases (deficiency, genetics, metabolism)