The fork protection complex generates DNA topological stress-induced DNA damage while ensuring full and faithful genome duplication

• 成果类型: Article
• 署名作者: Keszthelyi, Andrea; Mansoubi, Sahar; Whale, Alex; Houseley, Jonathan; Baxter, Jonathan
• 署名单位: University of Sussex; Islamic Azad University; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Babraham Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14605
• DOI: 10.1073/pnas.2413631121
• 发表日期: 2024-12-03
• 关键词: s-phase; replication forks; topoisomerase-ii; homologous recombination; genotoxic stress; mrc1; checkpoint; helicase; tipin; tof1

摘要

The fork protection complex (FPC), composed ofMrc1, 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.