Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA; email:
Annu Rev Biochem. 2018 Jun 20;87:217-238. doi: 10.1146/annurev-biochem-062917-011921. Epub 2018 Jan 3.
Accurate transmission of the genetic information requires complete duplication of the chromosomal DNA each cell division cycle. However, the idea that replication forks would form at origins of DNA replication and proceed without impairment to copy the chromosomes has proven naive. It is now clear that replication forks stall frequently as a result of encounters between the replication machinery and template damage, slow-moving or paused transcription complexes, unrelieved positive superhelical tension, covalent protein-DNA complexes, and as a result of cellular stress responses. These stalled forks are a major source of genome instability. The cell has developed many strategies for ensuring that these obstructions to DNA replication do not result in loss of genetic information, including DNA damage tolerance mechanisms such as lesion skipping, whereby the replisome jumps the lesion and continues downstream; template switching both behind template damage and at the stalled fork; and the error-prone pathway of translesion synthesis.
准确的遗传信息传递要求在每个细胞分裂周期中完整地复制染色体 DNA。然而，复制叉将在 DNA 复制起点形成并在不损害染色体的情况下继续进行的观点已被证明是幼稚的。现在很清楚，复制叉经常因复制机制与模板损伤、转录复合物移动缓慢或暂停、未缓解的正超螺旋张力、共价蛋白-DNA 复合物之间的相遇而停滞不前，并且作为细胞应激反应的结果。这些停滞的叉是基因组不稳定的主要来源。细胞已经开发了许多策略来确保这些 DNA 复制的阻碍不会导致遗传信息的丢失，包括 DNA 损伤容忍机制，例如绕过损伤，即复制体跳过损伤并继续下游；模板在模板损伤后和停滞叉处切换；以及跨损伤合成的易错途径。
