Department of Biomedical Sciences, Cornell University, T2-006C Veterinary Research Tower, Ithaca, NY 14853, U.S.A.
Biochem Soc Trans. 2018 Dec 17;46(6):1643-1651. doi: 10.1042/BST20180308. Epub 2018 Dec 4.
Eukaryotic cells continuously experience DNA damage that can perturb key molecular processes like DNA replication. DNA replication forks that encounter DNA lesions typically slow and may stall, which can lead to highly detrimental fork collapse if appropriate protective measures are not executed. Stabilization and protection of stalled replication forks ensures the possibility of effective fork restart and prevents genomic instability. Recent efforts from multiple laboratories have highlighted several proteins involved in replication fork remodeling and DNA damage response pathways as key regulators of fork stability. Homologous recombination factors such as RAD51, BRCA1, and BRCA2, along with components of the Fanconi Anemia pathway, are now known to be crucial for stabilizing stalled replication forks and preventing nascent strand degradation. Several checkpoint proteins have additionally been implicated in fork protection. Ongoing work in this area continues to shed light on a sophisticated molecular pathway that balances the action of DNA resection and fork protection to maintain genomic integrity, with important implications for the fate of both normal and malignant cells following replication stress.
真核细胞不断经历可能扰乱关键分子过程（如 DNA 复制）的 DNA 损伤。遇到 DNA 损伤的 DNA 复制叉通常会减速甚至停滞，如果不采取适当的保护措施，就可能导致严重的叉崩溃。稳定和保护停滞的复制叉确保了有效叉重新启动的可能性，并防止基因组不稳定。来自多个实验室的最新研究强调了几种参与复制叉重塑和 DNA 损伤反应途径的蛋白质，它们是叉稳定性的关键调节剂。同源重组因子，如 RAD51、BRCA1 和 BRCA2，以及范可尼贫血途径的成分，现在被认为对稳定停滞的复制叉和防止新生链降解至关重要。此外，几个检查点蛋白也被牵连到叉保护中。该领域的持续研究不断揭示出一个复杂的分子途径，该途径平衡了 DNA 切除和叉保护的作用，以维持基因组完整性，对复制应激后正常和恶性细胞的命运都有重要影响。
