Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, USA.
Cold Spring Harb Perspect Biol. 2013 Mar 1;5(3):a012914. doi: 10.1101/cshperspect.a012914.
One of the fundamental challenges facing the cell is to accurately copy its genetic material to daughter cells. When this process goes awry, genomic instability ensues in which genetic alterations ranging from nucleotide changes to chromosomal translocations and aneuploidy occur. Organisms have developed multiple mechanisms that can be classified into two major classes to ensure the fidelity of DNA replication. The first class includes mechanisms that prevent premature initiation of DNA replication and ensure that the genome is fully replicated once and only once during each division cycle. These include cyclin-dependent kinase (CDK)-dependent mechanisms and CDK-independent mechanisms. Although CDK-dependent mechanisms are largely conserved in eukaryotes, higher eukaryotes have evolved additional mechanisms that seem to play a larger role in preventing aberrant DNA replication and genome instability. The second class ensures that cells are able to respond to various cues that continuously threaten the integrity of the genome by initiating DNA-damage-dependent "checkpoints" and coordinating DNA damage repair mechanisms. Defects in the ability to safeguard against aberrant DNA replication and to respond to DNA damage contribute to genomic instability and the development of human malignancy. In this article, we summarize our current knowledge of how genomic instability arises, with a particular emphasis on how the DNA replication process can give rise to such instability.
细胞面临的一个基本挑战是准确地将其遗传物质复制到子细胞中。当这个过程出错时，就会出现基因组不稳定，其中会发生从核苷酸变化到染色体易位和非整倍体等各种遗传改变。生物体已经开发出多种机制，可以分为两大类，以确保 DNA 复制的保真度。第一类包括防止 DNA 复制过早起始并确保基因组在每个分裂周期中仅复制一次的机制。这些机制包括细胞周期蛋白依赖性激酶 (CDK) 依赖性机制和 CDK 非依赖性机制。虽然 CDK 依赖性机制在真核生物中基本保守，但高等真核生物已经进化出了似乎在防止异常 DNA 复制和基因组不稳定方面发挥更大作用的额外机制。第二类机制确保细胞能够通过启动 DNA 损伤依赖性“检查点”并协调 DNA 损伤修复机制来应对不断威胁基因组完整性的各种信号。防止异常 DNA 复制和应对 DNA 损伤的能力缺陷导致基因组不稳定和人类恶性肿瘤的发展。在本文中，我们总结了我们目前对基因组不稳定是如何产生的认识，特别强调了 DNA 复制过程如何导致这种不稳定性。
