Cdt1 modulates kinetochore-microtubule attachment stabilization via an Aurora B kinase-dependent mechanism

Shivangi Agarwal, Kyle Paul Smith, Yizhuo Zhou, Aussie Suzuki, Richard J. McKenney, Dileep Varma*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Robust kinetochore-microtubule (kMT) attachment is critical for accurate chromosome segregation. G2/M-specific depletion of human Cdt1 that localizes to kinetochores in an Ndc80 complex-dependent manner, leads to abnormal kMT attachments and mitotic arrest. This indicates an independent mitotic role for Cdt1 in addition to its prototypic function in DNA replication origin licensing. Here, we show that Cdt1 directly binds to microtubules (MTs). Endogenous or transiently expressed Cdt1 localizes to both mitotic spindle MTs and kinetochores. Deletion mapping of Cdt1 revealed that the regions comprising the middle and C-terminal winged-helix domains but lacking the N-terminal unstructured region was required for efficient MT-binding. Mitotic kinase Aurora B interacts with and phosphorylates Cdt1. Aurora B-phosphomimetic Cdt1 exhibited attenuated MT-binding and its cellular expression induced defective kMT attachments with a concomitant delay in mitotic progression. Thus we provide mechanistic insight into how Cdt1 affects overall kMT stability in an Aurora B kinase phosphorylation-dependent manner; which is envisioned to augment the MT-binding of the Ndc80 complex. eTOC summary • Cdt1 binds to microtubules• The middle and the C-terminal winged-helix domains of Cdt1 are involved in MT-binding• Aurora B Kinase phosphorylates Cdt1 and influences its MT-binding• Aurora B-mediated Cdt1 phosphorylation is necessary for kMT stability and mitotic progression

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Sep 27 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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