Activation of oncogenes disturbs a wide variety of cellular processes and induces physiological dysregulation of DNA replication, widely referred to as replication stress (RS). Oncogene-induced RS can cause replication forks to stall or collapse, thereby leading to DNA damage. While the DNA damage response (DDR) can provoke an anti-tumor barrier to prevent the development of cancer, a small subset of cells triggers replication stress tolerance (RST), allowing precancerous cells to survive, thereby promoting clonal expansion and genomic instability (GIN). Genomic instability (GIN) is a hallmark of cancer, driving genetic alterations ranging from nucleotide changes to aneuploidy. These alterations increase the probability of oncogenic events and create a heterogeneous cell population with an enhanced ability to evolve. This review explores how major oncogenes such as RAS, cyclin E, and MYC induce RS through diverse mechanisms. Additionally, we delve into the strategies employed by normal and cancer cells to tolerate RS and promote GIN. Understanding the intricate relationship between oncogene activation, RS, and GIN is crucial to better understand how cancer cells emerge and to develop potential cancer therapies that target these vulnerabilities.
癌基因的激活会扰乱多种细胞过程，并诱导DNA复制的生理失调，这种现象被广泛称为复制压力（RS）。癌基因诱导的复制压力可导致复制叉停滞或崩溃，进而引发DNA损伤。虽然DNA损伤应答（DDR）能够构建抗肿瘤屏障以阻止癌症发展，但一小部分细胞会触发复制压力耐受（RST），使癌前细胞得以存活，从而促进克隆扩增和基因组不稳定性（GIN）。基因组不稳定性是癌症的重要特征，可驱动从核苷酸改变到非整倍体等多种遗传变异。这些变异增加了致癌事件发生的概率，并形成具有更强进化能力的异质性细胞群体。本综述探讨了RAS、细胞周期蛋白E和MYC等主要癌基因如何通过不同机制诱导复制压力。此外，我们深入探讨了正常细胞和癌细胞为耐受复制压力并促进基因组不稳定性所采用的策略。理解癌基因激活、复制压力与基因组不稳定性之间的复杂关系，对于更好地认识癌细胞的产生机制以及开发针对这些薄弱环节的潜在癌症疗法至关重要。
Tolerance of Oncogene-Induced Replication Stress: A Fuel for Genomic Instability
肿瘤(癌症)患者之家