SUMOylation of DNA topoisomerase IIα regulates histone H3 kinase Haspin and H3 phosphorylation in mitosis.
DNA topoisomerase II (TOP2) plays a pivotal role in faithful chromosome separation through its strand-passaging activity that resolves tangled genomic DNA during mitosis. Additionally, TOP2 controls progression of mitosis by activating cell cycle checkpoints. Recent work showed that the enzymatically inert C-terminal domain (CTD) of TOP2 and its posttranslational modification are critical to this checkpoint regulation. However, the molecular mechanism has not yet been determined. By using Xenopus laevis egg extract, we found that SUMOylation of DNA topoisomerase IIα (TOP2A) CTD regulates the localization of the histone H3 kinase Haspin and phosphorylation of histone H3 at threonine 3 at the centromere, two steps known to be involved in the recruitment of the chromosomal passenger complex (CPC) to kinetochores in mitosis. Robust centromeric Haspin localization requires SUMOylated TOP2A CTD binding activity through SUMO-interaction motifs and the phosphorylation of Haspin. We propose a novel mechanism through which the TOP2 CTD regulates the CPC via direct interaction with Haspin at mitotic centromeres.
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045.
Makoto M
MM
Yoshida
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Lily
L
Ting
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Steven P
SP
Gygi
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045 azumay@ku.edu.
Yoshiaki
0000-0002-9634-6676
Y
Azuma
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D064107:Aurora Kinase B / Q000378:metabolism; D002503:Centromere / Q000378:metabolism / Q000502:physiology; D020090:Chromosome Segregation / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018386:Kinetochores / Q000378:metabolism / Q000502:physiology; D008938:Mitosis / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D058207:Sumoylation / Q000502:physiology*; D013912:Threonine / Q000378:metabolism; D014982:Xenopus laevis
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D013912:Threonine; D064107:Aurora Kinase B; D017346:Protein Serine-Threonine Kinases; D004250:DNA Topoisomerases, Type II