细胞周期蛋白依赖性激酶7-双胸苷激酶4通过对接位点介导的机制磷酸化微小染色体维持蛋白，以促进S期进程。
Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression.
作者信息
Sheu Yi-Jun, Stillman Bruce
机构信息
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
出版信息
Mol Cell. 2006 Oct 6;24(1):101-13. doi: 10.1016/j.molcel.2006.07.033.
Abstract
Origins of DNA replication are licensed in G1 by recruiting the minichromosome maintenance (MCM) proteins to form a prereplicative complex (pre-RC). Prior to initiation of DNA synthesis from each origin, a preinitiation complex (pre-IC) containing Cdc45 and other proteins is formed. We report that Cdc7-Dbf4 protein kinase (DDK) promotes assembly of a stable Cdc45-MCM complex exclusively on chromatin in S phase. In this complex, Mcm4 is hyperphosphorylated. Studies in vitro using purified DDK and Mcm4 demonstrate that hyperphosphorylation occurs at the Mcm4 N terminus. However, the DDK substrate specificity is conferred by an adjacent DDK-docking domain (DDD), sufficient for facilitating efficient phosphorylation of artificial phosphoacceptors in cis. Genetic evidence suggests that phosphorylation of Mcm4 by DDK is important for timely S phase progression and for cell viability upon overproduction of Cdc45. We suggest that DDK docks on and phosphorylates MCM proteins at licensed origins to promote proper assembly of pre-IC.
摘要
DNA复制起点在G1期通过招募微小染色体维持（MCM）蛋白形成前复制复合体（pre-RC）而获得许可。在从每个起点起始DNA合成之前，会形成一个包含Cdc45和其他蛋白的前起始复合体（pre-IC）。我们报告称，Cdc7-Dbf4蛋白激酶（DDK）专门在S期促进稳定的Cdc45-MCM复合体在染色质上的组装。在这个复合体中，Mcm4发生了超磷酸化。使用纯化的DDK和Mcm4进行的体外研究表明，超磷酸化发生在Mcm4的N末端。然而，DDK的底物特异性由相邻的DDK对接结构域（DDD）赋予，该结构域足以促进顺式人工磷酸受体的高效磷酸化。遗传学证据表明，DDK对Mcm4的磷酸化对于S期的及时进展以及Cdc45过量表达时的细胞活力很重要。我们认为，DDK在获得许可的起点上对接并磷酸化MCM蛋白，以促进pre-IC的正确组装。
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