Rampakakis E, Arvanitis D N, Di Paola D, Zannis-Hadjopoulos M
Department of Biochemistry, Goodman Cancer Centre, Montreal, Quebec, Canada.
J Cell Biochem. 2009 Mar 1;106(4):512-20. doi: 10.1002/jcb.22070.
DNA replication in eukaryotes is initiated at multiple replication origins distributed over the entire genome, which are normally activated once per cell cycle. Due to the complexity of the metazoan genome, the study of metazoan replication origins and their activity profiles has been less advanced than in simpler genome systems. DNA replication in eukaryotes involves many protein-protein and protein-DNA interactions, occurring in multiple stages. As in prokaryotes, control over the timing and frequency of initiation is exerted at the initiation site. A prerequisite for understanding the regulatory mechanisms of eukaryotic DNA replication is the identification and characterization of the cis-acting sequences that serve as replication origins and the trans-acting factors (proteins) that interact with them. Furthermore, in order to understand how DNA replication may become deregulated in malignant cells, the distinguishing features between normal and malignant origins of DNA replication as well as the proteins that interact with them must be determined. Based on advances that were made using simple genome model systems, several proteins involved in DNA replication have been identified. This review summarizes the current findings about metazoan origins of DNA replication and their interacting proteins as well as the role of chromatin structure in their regulation. Furthermore, progress in origin identification and isolation procedures as well as potential mechanisms to inhibit their activation in cancer development and progression are discussed.
真核生物中的DNA复制起始于分布在整个基因组中的多个复制起点，这些起点通常在每个细胞周期中被激活一次。由于后生动物基因组的复杂性，后生动物复制起点及其活性谱的研究比在更简单的基因组系统中要落后。真核生物中的DNA复制涉及许多蛋白质-蛋白质和蛋白质-DNA相互作用，发生在多个阶段。与原核生物一样，起始的时间和频率控制在起始位点进行。理解真核生物DNA复制调控机制的一个先决条件是鉴定和表征作为复制起点的顺式作用序列以及与它们相互作用的反式作用因子（蛋白质）。此外，为了理解DNA复制在恶性细胞中如何失控，必须确定正常和恶性DNA复制起点之间的区别特征以及与它们相互作用的蛋白质。基于使用简单基因组模型系统取得的进展，已经鉴定出几种参与DNA复制的蛋白质。本综述总结了关于后生动物DNA复制起点及其相互作用蛋白质的当前发现，以及染色质结构在其调控中的作用。此外，还讨论了起点鉴定和分离程序的进展以及在癌症发生和发展中抑制其激活的潜在机制。
