Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, BN1 9RQ, UK.
Nucleic Acids Res. 2021 May 21;49(9):4831-4847. doi: 10.1093/nar/gkab176.
To bypass a diverse range of fork stalling impediments encountered during genome replication, cells possess a variety of DNA damage tolerance (DDT) mechanisms including translesion synthesis, template switching, and fork reversal. These pathways function to bypass obstacles and allow efficient DNA synthesis to be maintained. In addition, lagging strand obstacles can also be circumvented by downstream priming during Okazaki fragment generation, leaving gaps to be filled post-replication. Whether repriming occurs on the leading strand has been intensely debated over the past half-century. Early studies indicated that both DNA strands were synthesised discontinuously. Although later studies suggested that leading strand synthesis was continuous, leading to the preferred semi-discontinuous replication model. However, more recently it has been established that replicative primases can perform leading strand repriming in prokaryotes. An analogous fork restart mechanism has also been identified in most eukaryotes, which possess a specialist primase called PrimPol that conducts repriming downstream of stalling lesions and structures. PrimPol also plays a more general role in maintaining efficient fork progression. Here, we review and discuss the historical evidence and recent discoveries that substantiate repriming as an intrinsic replication restart pathway for maintaining efficient genome duplication across all domains of life.
为了绕过基因组复制过程中遇到的各种叉子停滞障碍，细胞拥有多种 DNA 损伤容忍（DDT）机制，包括跨损伤合成、模板转换和叉子反转。这些途径的功能是绕过障碍物，保持有效的 DNA 合成。此外，滞后链障碍也可以通过冈崎片段生成过程中的下游引发来避免，从而留下复制后填补的缺口。在过去的半个世纪里，关于领头链上是否会重新引发一直存在激烈的争论。早期的研究表明，两条 DNA 链都是不连续合成的。尽管后来的研究表明，领头链的合成是连续的，导致了首选的半不连续复制模型。然而，最近的研究已经证实，复制起始酶可以在原核生物中进行领头链重新引发。大多数真核生物也发现了类似的叉子重新启动机制，它们拥有一种专门的起始酶 PrimPol，可以在停滞损伤和结构的下游进行重新引发。PrimPol 在维持有效的叉子进展方面也起着更普遍的作用。在这里，我们回顾和讨论了支持重新引发作为维持所有生命领域高效基因组复制的内在复制重新启动途径的历史证据和最近的发现。
