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Haspin inhibitors reveal centromeric functions of Aurora B in chromosome segregation.

Authors
  • Wang, Fangwei1
  • Ulyanova, Natalia P
  • Daum, John R
  • Patnaik, Debasis
  • Kateneva, Anna V
  • Gorbsky, Gary J
  • Higgins, Jonathan M G
  • 1 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Type
Published Article
Journal
The Journal of Cell Biology
Publisher
The Rockefeller University Press
Publication Date
Oct 15, 2012
Volume
199
Issue
2
Pages
251–268
Identifiers
DOI: 10.1083/jcb.201205106
PMID: 23071152
Source
Medline
License
Unknown

Abstract

Haspin phosphorylates histone H3 at threonine-3 (H3T3ph), providing a docking site for the Aurora B complex at centromeres. Aurora B functions to correct improper kinetochore-microtubule attachments and alert the spindle checkpoint to the presence of misaligned chromosomes. We show that Haspin inhibitors decreased H3T3ph, resulting in loss of centromeric Aurora B and reduced phosphorylation of centromere and kinetochore Aurora B substrates. Consequently, metaphase chromosome alignment and spindle checkpoint signaling were compromised. These effects were phenocopied by microinjection of anti-H3T3ph antibodies. Retargeting Aurora B to centromeres partially restored checkpoint signaling and Aurora B-dependent phosphorylation at centromeres and kinetochores, bypassing the need for Haspin activity. Haspin inhibitors did not obviously affect phosphorylation of histone H3 at serine-10 (H3S10ph) by Aurora B on chromosome arms but, in Aurora B reactivation assays, recovery of H3S10ph was delayed. Haspin inhibitors did not block Aurora B localization to the spindle midzone in anaphase or Aurora B function in cytokinesis. Thus, Haspin inhibitors reveal centromeric roles of Aurora B in chromosome movement and spindle checkpoint signaling.

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