The Francis Crick Institute, London, United Kingdom.
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Cancer Discov. 2018 May;8(5):537-555. doi: 10.1158/2159-8290.CD-17-1461. Epub 2018 Apr 13.
Oncogene activation disturbs cellular processes and accommodates a complex landscape of changes in the genome that contribute to genomic instability, which accelerates mutation rates and promotes tumorigenesis. Part of this cellular turmoil involves deregulation of physiologic DNA replication, widely described as replication stress. Oncogene-induced replication stress is an early driver of genomic instability and is attributed to a plethora of factors, most notably aberrant origin firing, replication-transcription collisions, reactive oxygen species, and defective nucleotide metabolism. Replication stress is a fundamental step and an early driver of tumorigenesis and has been associated with many activated oncogenes. Deciphering the mechanisms that contribute to the replication stress response may provide new avenues for targeted cancer treatment. In this review, we discuss the latest findings on the DNA replication stress response and examine the various mechanisms through which activated oncogenes induce replication stress.
癌基因激活扰乱细胞过程，并适应基因组中导致基因组不稳定的复杂变化景观，从而加速突变率并促进肿瘤发生。这种细胞混乱的一部分涉及生理 DNA 复制的失调，广泛描述为复制应激。癌基因诱导的复制应激是基因组不稳定的早期驱动因素，归因于多种因素，尤其是异常起始点火、复制-转录碰撞、活性氧和核苷酸代谢缺陷。复制应激是肿瘤发生的基本步骤和早期驱动因素，并与许多激活的癌基因有关。解析导致复制应激反应的机制可能为癌症的靶向治疗提供新的途径。在这篇综述中，我们讨论了 DNA 复制应激反应的最新发现，并研究了激活的癌基因诱导复制应激的各种机制。
