Jones Peter D, Kaiser Michael A, Ghaderi Najafabadi Maryam, McVey David G, Beveridge Allan J, Schofield Christine L, Samani Nilesh J, Webb Tom R
From the Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP and.
Horizon Discovery Limited, 7100 Cambridge Research Park, Waterbeach, Cambridge CB25 9TL, United Kingdom.
J Biol Chem. 2016 Jul 29;291(31):16318-27. doi: 10.1074/jbc.M116.734020. Epub 2016 May 19.
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.
全基因组关联研究迄今已鉴定出多个与冠状动脉疾病（CAD）相关的基因座；然而，对于这些基因座中的大多数，它们影响CAD风险的机制尚不清楚。与CAD相关的7q32.2基因座不同寻常之处在于，其主要变异体rs11556924与任何其他变异体均不存在强连锁不平衡，并在编码NIPA的ZC3HC1中引入了编码变化。在本研究中，我们表明rs11556924多态性与风险变异体中NIPA较低的调节性磷酸化相关，导致NIPA具有更高的活性。使用基因组编辑方法，我们表明这会导致细胞核中细胞周期蛋白B1稳定性有效降低，从而减缓其细胞核积累。通过干扰细胞核中细胞周期蛋白B1积累的速率，rs11556924改变了有丝分裂进程的调节，导致有丝分裂延长。这项研究表明，ZC3HC1中与CAD相关的编码多态性改变了NIPA对细胞周期调节的动力学。
