Cdt1 stabilizes kinetochore-microtubule attachments via an Aurora B kinase-dependent mechanism

The Journal of Cell Biology
Shivangi AgarwalDileep Varma

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 were 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.

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Citations

Jun 23, 2020·Biochemistry. Biokhimii︠a︡·N B UstinovN B Gudimchuk
Aug 26, 2020·PLoS Genetics·Yizhuo ZhouJeanette Gowen Cook
May 22, 2020·The Journal of Cell Biology·Alexandra F LongSophie Dumont
Aug 28, 2020·Essays in Biochemistry·Amit RahiDileep Varma
Jun 17, 2020·Cell Cycle·João BarbosaClaudio Sunkel
Dec 7, 2020·Cytoskeleton·Joseph Y OngJorge Z Torres
Feb 5, 2021·Proceedings of the National Academy of Sciences of the United States of America·Ukhyun JoYves Pommier
May 28, 2019·Current Opinion in Cell Biology·Alexandra F LongSophie Dumont

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Methods Mentioned

BETA
NMR
fluorescence microscopy
Pulldown
transmission electron microscopy
acetylation
transfection

Software Mentioned

DiaTrack
Kymograph
Manager
NIS Elements
ImageJ
Scaffold Q +
Phyre2
Micro
Mascot
PyMol

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