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The Coronary Artery Disease Associated Coding Variant in Zinc finger C3HC-type containing 1 (ZC3HC1) Affects Cell Cycle Regulation.

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journal contribution
posted on 14.06.2016, 11:41 by Peter D. Jones, Michael A. Kaiser, Maryam Ghaderi Najafabadi, David G. McVey, Allan J. Beveridge, Christine L. Schofield, Nilesh J. Samani, Tom R. Webb
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.

History

Citation

Journal of Biological Chemistry, 2016, doi: 10.1074/jbc.M116.734020

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

AM (Accepted Manuscript)

Published in

Journal of Biological Chemistry

Publisher

American Society for Biochemistry and Molecular Biology

eissn

1083-351X

Acceptance date

19/05/2016

Copyright date

2016

Available date

14/06/2016

Publisher version

http://www.jbc.org/content/early/2016/05/19/jbc.M116.734020

Language

en