Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9RQ, United Kingdom.
Biology Department, North Tehran Branch, Islamic Azad University, Tehran 1477893855, Iran.
Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2413631121. doi: 10.1073/pnas.2413631121. Epub 2024 Nov 26.
The fork protection complex (FPC), composed of Mrc1, Tof1, and Csm3, supports rapid and stable DNA replication. Here, we show that FPC activity also introduces DNA damage by increasing DNA topological stress during replication. Mrc1 action increases DNA topological stress during plasmid replication, while Mrc1 or Tof1 activity causes replication stress and DNA damage within topologically constrained regions. We show that the recruitment of Top1 to the fork by Tof1 suppresses the DNA damage generated in these loci. While FPC activity introduces some DNA damage due to increased topological stress, the FPC is also necessary to prevent DNA damage in long replicons across the genome, indicating that the FPC is required for complete and faithful genome duplication. We conclude that FPC regulation must balance ensuring full genome duplication through rapid replication with minimizing the consequential DNA topological stress-induced DNA damage caused by rapid replication through constrained regions.
叉保护复合物（FPC）由 Mrc1、Tof1 和 Csm3 组成，支持快速和稳定的 DNA 复制。在这里，我们表明 FPC 活性还通过在复制过程中增加 DNA 拓扑结构应力来引入 DNA 损伤。Mrc1 作用在质粒复制过程中增加 DNA 拓扑结构应力，而 Mrc1 或 Tof1 活性导致拓扑结构约束区域内的复制应激和 DNA 损伤。我们表明，Tof1 将 Top1 招募到叉上可抑制这些位点产生的 DNA 损伤。虽然 FPC 活性会因拓扑结构应力增加而导致一些 DNA 损伤，但 FPC 对于在整个基因组中复制长复制子的 DNA 损伤也是必需的，这表明 FPC 对于完整和忠实的基因组复制是必需的。我们的结论是，FPC 调节必须在通过快速复制确保完整基因组复制与通过约束区域快速复制最小化随之而来的 DNA 拓扑结构应激诱导的 DNA 损伤之间取得平衡。
