O-GlcNAcase is essential for embryonic development and maintenance of genomic stability.
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.
Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea.
Yong Ryoul
YR
Yang
Minseok
M
Song
Ho
H
Lee
Yoon
Y
Jeon
Eun-Jeong
EJ
Choi
Hyun-Jun
HJ
Jang
Hyo Youl
HY
Moon
Ha-Young
HY
Byun
Eung-Kyun
EK
Kim
Dae Hyun
DH
Kim
Mi Nam
MN
Lee
Ara
A
Koh
Jaewang
J
Ghim
Jang Hyun
JH
Choi
Whaseon
W
Lee-Kwon
Kyong Tai
KT
Kim
Sung Ho
SH
Ryu
Pann-Ghill
PG
Suh
D000367:Age Factors; D000818:Animals; D002460:Cell Line; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D042822:Genomic Instability; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase