DNA Replication and Cancer Group, Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.
Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Medical Biochemistry and Biophysics, Division of Genome Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
DNA Repair (Amst). 2019 Sep;81:102654. doi: 10.1016/j.dnarep.2019.102654. Epub 2019 Jul 8.
Replication of DNA is a fundamental biological process that ensures precise duplication of the genome and thus safeguards inheritance. Any errors occurring during this process must be repaired before the cell divides, by activating the DNA damage response (DDR) machinery that detects and corrects the DNA lesions. Consistent with its significance, DNA replication is under stringent control, both spatial and temporal. Defined regions of the genome are replicated at specific times during S phase and the speed of replication fork progression is adjusted to fully replicate DNA in pace with the cell cycle. Insults that impair DNA replication cause replication stress (RS), which can lead to genomic instability and, potentially, to cell transformation. In this perspective, we review the current concept of replication stress, including the recent findings on the effects of accelerated fork speed and their impact on genomic (in)stability. We discuss in detail the Fork Speed Regulatory Network (FSRN), an integrated molecular machinery that regulates the velocity of DNA replication forks. Finally, we explore the potential for targeting FSRN components as an avenue to treat cancer.
DNA 的复制是一个基本的生物学过程，它确保了基因组的精确复制，从而保障了遗传。在这个过程中发生的任何错误都必须在细胞分裂前通过激活 DNA 损伤反应（DDR）机制来修复，该机制可以检测和纠正 DNA 损伤。由于其重要性，DNA 复制受到严格的时空控制。基因组的特定区域在 S 期的特定时间进行复制，复制叉的前进速度也会进行调整，以与细胞周期同步完成 DNA 的完全复制。任何损害 DNA 复制的因素都会导致复制应激（RS），这可能导致基因组不稳定，并可能导致细胞转化。在这篇观点文章中，我们回顾了复制应激的最新概念，包括最近关于加速叉速度的影响及其对基因组（不）稳定性的影响的发现。我们详细讨论了叉速调控网络（FSRN），这是一个整合的分子机制，调节 DNA 复制叉的速度。最后，我们探讨了靶向 FSRN 组件作为治疗癌症的一种途径的可能性。
