Probing the catalytic functions of Bub1 kinase using the small molecule inhibitors BAY-320 and BAY-524

ELife
Anna P BaronErich A Nigg

Abstract

The kinase Bub1 functions in the spindle assembly checkpoint (SAC) and in chromosome congression, but the role of its catalytic activity remains controversial. Here, we use two novel Bub1 inhibitors, BAY-320 and BAY-524, to demonstrate potent Bub1 kinase inhibition both in vitro and in intact cells. Then, we compared the cellular phenotypes of Bub1 kinase inhibition in HeLa and RPE1 cells with those of protein depletion, indicative of catalytic or scaffolding functions, respectively. Bub1 inhibition affected chromosome association of Shugoshin and the chromosomal passenger complex (CPC), without abolishing global Aurora B function. Consequently, inhibition of Bub1 kinase impaired chromosome arm resolution but exerted only minor effects on mitotic progression or SAC function. Importantly, BAY-320 and BAY-524 treatment sensitized cells to low doses of Paclitaxel, impairing both chromosome segregation and cell proliferation. These findings are relevant to our understanding of Bub1 kinase function and the prospects of targeting Bub1 for therapeutic applications.

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Citations

Aug 6, 2016·Frontiers in Genetics·Stefano Ferrari, Christian Gentili
Oct 5, 2016·The Journal of Cell Biology·Patrick M RedliAnna Santamaria
Jan 20, 2017·Nature·Alex C FaesenAndrea Musacchio
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Oct 8, 2021·Scientific Reports·Katerina SoupsanaSpyros Georgatos

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Methods Mentioned

BETA
electrophoresis
transfection
flow cytometry
FRET
fluorescence microscopy
biosensors
fluorescence imaging
fluorescence recovery after photobleaching
size exclusion chromatography
profiler

Software Mentioned

Prism
SlideBook
ImageJ
DiscoverX Kinome Scan
MetaMorph
Cell Profiler
GraphPad
SoftWorx
GraphPad Prism

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