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|Title:||The Coronary Artery Disease Associated Coding Variant in Zinc finger C3HC-type containing 1 (ZC3HC1) Affects Cell Cycle Regulation.|
|Authors:||Jones, Peter D.|
Kaiser, Michael A.
Ghaderi Najafabadi, Maryam
McVey, David G.
Beveridge, Allan J.
Schofield, Christine L.
Samani, Nilesh J.
Webb, Tom R.
|Publisher:||American Society for Biochemistry and Molecular Biology|
|Citation:||Journal of Biological Chemistry, 2016, doi: 10.1074/jbc.M116.734020|
|Abstract:||Genome wide association studies have to date identified multiple coronary artery disease (CAD) associated loci; however, for most of these loci the mechanism by which they affect CAD risk is unclear. The CAD-associated locus 7q32.2 is unusual in that the lead variant, rs11556924, is not in strong linkage disequilibrium with any other variant and introduces a coding change in ZC3HC1, which encodes NIPA. In this study, we show that rs11556924 polymorphism is associated with lower regulatory phosphorylation of NIPA in the risk variant, resulting in NIPA with higher activity. Using a genome editing approach we show that this causes an effective decrease in Cyclin-B1 stability in the nucleus, thereby slowing its nuclear accumulation. By perturbing the rate of nuclear Cyclin-B1 accumulation, rs11556924 alters the regulation of mitotic progression resulting in an extended mitosis. This study shows that the CAD-associated coding polymorphism in ZC3HC1 alters the dynamics of cell-cycle regulation by NIPA.|
|Rights:||Copyright © American Society for Biochemistry and Molecular Biology, 2016. This article is distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.|
|Appears in Collections:||Published Articles, Dept. of Cardiovascular Sciences|
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