• Open Access

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

Authors

  • Yong Ryoul Yang,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
    2. School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea
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  • Minseok Song,

    1. Department of Psychiatry, Weill Cornell Medical College, New York, NY 10065, USA
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  • Ho Lee,

    1. Cancer Experimental Resources Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea
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  • Yoon Jeon,

    1. Cancer Experimental Resources Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea
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  • Eun-Jeong Choi,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
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  • Hyun-Jun Jang,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
    2. School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea
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  • Hyo Youl Moon,

    1. School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea
    2. School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea
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  • Ha-Young Byun,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
    2. School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea
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  • Eung-Kyun Kim,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
    2. School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea
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  • Dae Hyun Kim,

    1. School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea
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  • Mi Nam Lee,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
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  • Ara Koh,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
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  • Jaewang Ghim,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
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  • Jang Hyun Choi,

    1. Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute, Boston, MA 02115, USA
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  • Whaseon Lee-Kwon,

    1. School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea
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  • Kyong Tai Kim,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
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  • Sung Ho Ryu,

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
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  • Pann-Ghill Suh

    1. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
    2. School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea
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Pann-Ghill Suh, Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea. Tel.: +82 52 217 2621; fax: +82 52 217 2609; e-mail:pgsuh@unist.ac.kr

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.

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