O-linked N-acetylglucosamine cycling regulates mitotic spindle organization.
Any defects in the correct formation of the mitotic spindle will lead to chromosomal segregation errors, mitotic arrest, or aneuploidy. We demonstrate that O-linked N-acetylglucosamine (O-GlcNAc), a post-translational modification of serine and threonine residues in nuclear and cytoplasmic proteins, regulates spindle function. In O-GlcNAc transferase or O-GlcNAcase gain of function cells, the mitotic spindle is incorrectly assembled. Chromosome condensation and centrosome assembly is impaired in these cells. The disruption in spindle architecture is due to a reduction in histone H3 phosphorylation by Aurora kinase B. However, gain of function cells treated with the O-GlcNAcase inhibitor Thiamet-G restored the assembly of the spindle and partially rescued histone phosphorylation. Together, these data suggest that the coordinated addition and removal of O-GlcNAc, termed O-GlcNAc cycling, regulates mitotic spindle organization and provides a potential new perspective on how O-GlcNAc regulates cellular events.
Department of Biochemistry and Molecular Biology.
Ee Phie
EP
Tan
Department of Biochemistry and Molecular Biology.
Sarah
S
Caro
Department of Biochemistry and Molecular Biology.
Anish
A
Potnis
Department of Biochemistry and Molecular Biology.
Christopher
C
Lanza
Department of Biochemistry and Molecular Biology; Department of KUMC Cancer Center; Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas 64108. Electronic address: cslawson@kumc.edu.
Chad
C
Slawson
D000117:Acetylglucosamine / Q000378:metabolism*; D002877:Chromosomes, Human / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005964:Glucosyltransferases / Q000378:metabolism*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D011714:Pyrans / Q000494:pharmacology; D008941:Spindle Apparatus / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006657:Histones; D011714:Pyrans; D013844:Thiazoles; C572247:thiamet G; D005964:Glucosyltransferases; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine
Cell Cycle; Glycosylation; Mitosis; Mitotic Spindle; Phosphorylation