CoA synthase regulates mitotic fidelity via CBP-mediated acetylation.

Date
2018-03-12
Authors
Lin, Chao-Chieh
Kitagawa, Mayumi
Tang, Xiaohu
Hou, Ming-Hsin
Wu, Jianli
Qu, Dan Chen
Srinivas, Vinayaka
Liu, Xiaojing
Thompson, J Will
Mathey-Prevot, Bernard
Yao, Tso-Pang
Lee, Sang Hyun
Chi, Jen-Tsan
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(13 total)
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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
Conference
Subject
Cell Line
Humans
Transferases
Cell Cycle Proteins
Microtubule-Associated Proteins
Nuclear Proteins
Mitosis
Protein Binding
Acetylation
CREB-Binding Protein
Aurora Kinase A
Permalink
https://hdl.handle.net/10161/22379
Published Version (Please cite this version)
10.1038/s41467-018-03422-6
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Scholars@Duke

Chi

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
Mathey-Prevot

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
Thompson

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.
Yao

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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