Masai Hisao, You Zhiying, Arai Ken-ichi
Department of Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
IUBMB Life. 2005 Apr-May;57(4-5):323-35. doi: 10.1080/15216540500092419.
DNA replication is a key event of cell proliferation and the final target of signal transduction induced by growth factor stimulation. It is also strictly regulated during the ongoing cell cycle so that it occurs only once during S phase and that all the genetic materials are faithfully duplicated. DNA replication may be arrested or temporally inhibited due to a varieties of internal and external causes. Cells have developed intricate mechanisms to cope with the arrested replication forks to minimize the adversary effect on the stable maintenance of genetic materials. Helicases play a central role in DNA replication. In eukaryotes, MCM (minichromosome maintenance) protein complex plays essential roles as a replicative helicase. MCM4-6-7 complex possesses intrinsic DNA helicase activity which translocates on single-stranded DNA form 3' to 5'. Mammalian MCM4-6-7 helicase and ATPase activities are specifically stimulated by the presence of thymine-rich single-stranded DNA sequences onto which it is loaded. The activation appears to depend on the thymine content of this single-strand, and sequences derived from human replication origins can serve as potent activators of the MCM helicase. MCM is a prime target of Cdc7 kinase, known to be essential for activation of replication origins. We will discuss how the MCM may be activated at the replication origins by template DNA, phosphorylation, and interaction with other replicative proteins, and will present a model of how activation of MCM helicase by specific sequences may contribute to selection of replication initiation sites in higher eukaryotes.
DNA复制是细胞增殖的关键事件，也是生长因子刺激诱导的信号转导的最终靶点。在正在进行的细胞周期中，它也受到严格调控，以便在S期仅发生一次，并且所有遗传物质都被忠实地复制。由于各种内部和外部原因，DNA复制可能会停滞或暂时受到抑制。细胞已经发展出复杂的机制来应对停滞的复制叉，以尽量减少对遗传物质稳定维持的不利影响。解旋酶在DNA复制中起核心作用。在真核生物中，MCM（微小染色体维持）蛋白复合体作为复制性解旋酶发挥着重要作用。MCM4-6-7复合体具有内在的DNA解旋酶活性，可沿单链DNA从3'向5'方向移位。富含胸腺嘧啶的单链DNA序列的存在可特异性刺激哺乳动物MCM4-6-7解旋酶和ATP酶活性，MCM4-6-7复合体可结合于该序列上。这种激活似乎取决于该单链的胸腺嘧啶含量，并且源自人类复制起点的序列可作为MCM解旋酶的有效激活剂。MCM是Cdc7激酶的主要靶点，已知Cdc7激酶对复制起点的激活至关重要。我们将讨论MCM如何在复制起点被模板DNA、磷酸化以及与其他复制蛋白的相互作用激活，并将提出一个模型，说明特定序列对MCM解旋酶的激活如何有助于高等真核生物中复制起始位点的选择。
