DNA合成的起始反应是人染色体DNA复制过程中的核心过程。它们分为两个主要过程:复制起点的启动事件,每个复制子的前导链合成的开始,以及在滞后链DNA合成过程中发生的许多起始事件。此外,第三种机制是复制叉失速后DNA合成的重新开始,当DNA损伤阻碍DNA合成的进展时发生。在复制起点的前导链合成的启动在多个水平上被调节,从起源识别到复制解旋酶的组装和激活,Cdc45-MCM2-7-GINS(CMG)复合物。此外,CMG复合物与真核复制DNA聚合酶的多重相互作用,DNA聚合酶α-蛋白酶,DNA聚合酶δ和ε,在复制叉在前导和滞后链DNA合成的起始反应机制中起关键作用。这些相互作用对于在未受干扰和停滞的复制叉上启动信号也很重要,“复制压力”事件,通过ATR(ATM-Rad3相关蛋白激酶)。这些过程对于将细胞的遗传信息准确地传递给它们的女儿至关重要。因此,这些过程中的失败和功能障碍会导致基因组不稳定,导致遗传疾病,包括癌症.在他们有影响力的评论“癌症的标志:新维度”中,因此,Hanahan和Weinberg(2022)将基因组不稳定性称为癌细胞发育过程中的基本功能。近年来,对人类DNA复制的起始过程和机制的理解在各个层面都取得了实质性进展,这将在审查中讨论。
The initiation reactions of DNA synthesis are central processes during human chromosomal DNA replication. They are separated into two main processes: the initiation events at replication origins, the start of the leading strand synthesis for each replicon, and the numerous initiation events taking place during lagging strand DNA synthesis. In addition, a third mechanism is the re-initiation of DNA synthesis after replication fork stalling, which takes place when DNA lesions hinder the progression of DNA synthesis. The initiation of leading strand synthesis at replication origins is regulated at multiple levels, from the origin recognition to the assembly and activation of replicative helicase, the Cdc45-MCM2-7-GINS (CMG) complex. In addition, the multiple interactions of the CMG complex with the eukaryotic replicative DNA polymerases, DNA polymerase α-primase, DNA polymerase δ and ε, at replication forks play pivotal roles in the mechanism of the initiation reactions of leading and lagging strand DNA synthesis. These interactions are also important for the initiation of signalling at unperturbed and stalled replication forks, \"replication stress\" events, via ATR (ATM-Rad 3-related protein kinase). These processes are essential for the accurate transfer of the cells\' genetic information to their daughters. Thus, failures and dysfunctions in these processes give rise to genome instability causing genetic diseases, including cancer. In their influential review \"Hallmarks of Cancer: New Dimensions\", Hanahan and Weinberg (2022) therefore call genome instability a fundamental function in the development process of cancer cells. In recent years, the understanding of the initiation processes and mechanisms of human DNA replication has made substantial progress at all levels, which will be discussed in the review.