CoA synthase regulates mitotic fidelity via CBP-mediated acetylation.
Abstract
The temporal activation of kinases and timely ubiquitin-mediated degradation is central
to faithful mitosis. Here we present evidence that acetylation controlled by Coenzyme
A synthase (COASY) and acetyltransferase CBP constitutes a novel mechanism that ensures
faithful mitosis. We found that COASY knockdown triggers prolonged mitosis and multinucleation.
Acetylome analysis reveals that COASY inactivation leads to hyper-acetylation of proteins
associated with mitosis, including CBP and an Aurora A kinase activator, TPX2. During
early mitosis, a transient CBP-mediated TPX2 acetylation is associated with TPX2 accumulation
and Aurora A activation. The recruitment of COASY inhibits CBP-mediated TPX2 acetylation,
promoting TPX2 degradation for mitotic exit. Consistently, we detected a stage-specific
COASY-CBP-TPX2 association during mitosis. Remarkably, pharmacological and genetic
inactivation of CBP effectively rescued the mitotic defects caused by COASY knockdown.
Together, our findings uncover a novel mitotic regulation wherein COASY and CBP coordinate
an acetylation network to enforce productive mitosis.
Type
ConferenceSubject
Cell LineHumans
Transferases
Cell Cycle Proteins
Microtubule-Associated Proteins
Nuclear Proteins
Mitosis
Protein Binding
Acetylation
CREB-Binding Protein
Aurora Kinase A
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https://hdl.handle.net/10161/22379Published Version (Please cite this version)
10.1038/s41467-018-03422-6Collections
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Show full item recordScholars@Duke
Jen-Tsan Ashley Chi
Associate Professor in Molecular Genetics and Microbiology
We are using functional genomic approaches to investigate the nutrient signaling and
stress adaptations of cancer cells when exposed to various nutrient deprivations and
microenvironmental stress conditions. Recently, we focus on two areas. First, we are
elucidating the genetic determinants and disease relevance of ferroptosis, a newly
recognized form of cell death. Second, we have identified the mammalian stringent
response pathway which is highly similar to bacterial stringent response, but
Bernard Mathey-Prevot
Research Professor of Pharmacology & Cancer Biology
The central focus of the lab is to understand how signaling pathway architecture and
integration result in specific cell fates and how these properties have been hijacked
in cancer cells. In particular, we are interested in assessing the extent to which
cell-to-cell heterogeneity can affect the temporal dynamics and regulation of signaling
pathways. We are focusing on the E2F/Rb network and have established a platform to
follow in real time the activation and expression of E2F1 at the
J. Will Thompson
Assistant Research Professor of Pharmacology & Cancer Biology
Dr. Thompson's research focuses on the development and deployment of proteomics and
metabolomics mass spectrometry techniques for the analysis of biological systems.
He is the Assistant Director of the Proteomics and Metabolomics Shared Resource in
the Duke School of Medicine. In this role, he enjoys utilizing mass spectrometry 'omics
techniques in research collaborations with investigators throughout the Duke community.
Tso-Pang Yao
Professor of Pharmacology and Cancer Biology
My laboratory studies the regulatory functions of protein acetylation in cell signaling
and human disease. We focus on a class of protein deacetylases, HDACs, which we have
discovered versatile functions beyond gene transcription. We wish to use knowledge
of HDAC biology to develop smart and rational clinical strategies for HDAC inhibitors,
a growing class of compounds that show potent anti-tumor and other clinically relevant
activities. Currently, there two major research major areas
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