Evertts Adam G, Coller Hilary A
Princeton University, Princeton, NJ, USA.
Genes Cancer. 2012 Nov;3(11-12):678-96. doi: 10.1177/1947601912474891.
In bacteria, replication is a carefully orchestrated event that unfolds the same way for each bacterium and each cell division. The process of DNA replication in bacteria optimizes cell growth and coordinates high levels of simultaneous replication and transcription. In metazoans, the organization of replication is more enigmatic. The lack of a specific sequence that defines origins of replication has, until recently, severely limited our ability to define the organizing principles of DNA replication. This question is of particular importance as emerging data suggest that replication stress is an important contributor to inherited genetic damage and the genomic instability in tumors. We consider here the replication program in several different organisms including recent genome-wide analyses of replication origins in humans. We review recent studies on the role of cytosine methylation in replication origins, the role of transcriptional looping and gene gating in DNA replication, and the role of chromatin's 3-dimensional structure in DNA replication. We use these new findings to consider several questions surrounding DNA replication in metazoans: How are origins selected? What is the relationship between replication and transcription? How do checkpoints inhibit origin firing? Why are there early and late firing origins? We then discuss whether oncogenes promote cancer through a role in DNA replication and whether errors in DNA replication are important contributors to the genomic alterations and gene fusion events observed in cancer. We conclude with some important areas for future experimentation.
在细菌中，复制是一个精心编排的过程，每个细菌和每次细胞分裂都以相同的方式进行。细菌中的DNA复制过程优化了细胞生长，并协调了高水平的同时复制和转录。在多细胞动物中，复制的组织方式更加神秘。直到最近，由于缺乏定义复制起点的特定序列，我们定义DNA复制组织原则的能力受到了严重限制。随着新出现的数据表明复制应激是遗传损伤和肿瘤基因组不稳定的重要因素，这个问题尤为重要。我们在这里考虑几种不同生物体中的复制程序，包括最近对人类复制起点的全基因组分析。我们回顾了关于胞嘧啶甲基化在复制起点中的作用、转录环化和基因门控在DNA复制中的作用以及染色质三维结构在DNA复制中的作用的最新研究。我们利用这些新发现来思考围绕多细胞动物DNA复制的几个问题：复制起点是如何选择的？复制与转录之间的关系是什么？检查点如何抑制复制起点的激发？为什么会有早期和晚期激发的复制起点？然后我们讨论癌基因是否通过在DNA复制中的作用促进癌症，以及DNA复制错误是否是癌症中观察到的基因组改变和基因融合事件的重要因素。我们最后提出了一些未来实验的重要领域。
