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The Coronary Artery Disease-associated Coding Variant in Zinc Finger C3HC-type Containing 1 (ZC3HC1) Affects Cell Cycle Regulation.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2016 Jul 29; Vol. 291 (31), pp. 16318-27. Date of Electronic Publication: 2016 May 19. - Publication Year :
- 2016
-
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.<br /> (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Cell Line
Cyclin B1 genetics
Cyclin B1 metabolism
Humans
Zinc Fingers genetics
Adaptor Proteins, Signal Transducing genetics
Adaptor Proteins, Signal Transducing metabolism
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Coronary Artery Disease genetics
Coronary Artery Disease metabolism
Genetic Loci
Linkage Disequilibrium
Mitosis genetics
Nuclear Proteins genetics
Nuclear Proteins metabolism
Polymorphism, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 291
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27226629
- Full Text :
- https://doi.org/10.1074/jbc.M116.734020