DNA lesions induced by replication stress trigger mitotic aberration and tetraploidy development.

During tumorigenesis, cells acquire immortality in association with the development of genomic instability. However, it is still elusive how genomic instability spontaneously generates during the process of tumorigenesis. Here, we show that precancerous DNA lesions induced by oncogene acceleration, which induce situations identical to the initial stages of cancer development, trigger tetraploidy/aneuploidy generation in association with mitotic aberration. Although oncogene acceleration primarily induces DNA replication stress and the resulting lesions in the S phase, these lesions are carried over into the M phase and cause cytokinesis failure and genomic instability. Unlike directly induced DNA double-strand breaks, DNA replication stress-associated lesions are cryptogenic and pass through cell-cycle checkpoints due to limited and ineffective activation of checkpoint factors. Furthermore, since damaged M-phase cells still progress in mitotic steps, these cells result in chromosomal mis-segregation, cytokinesis failure and the resulting tetraploidy generation. Thus, our results reveal a process of genomic instability generation triggered by precancerous DNA replication stress.

在肿瘤发生过程中，细胞随着基因组不稳定性的发展而获得永生能力。然而，在肿瘤发生过程中基因组不稳定性是如何自发产生的仍然不清楚。在此，我们表明由癌基因加速诱导的癌前DNA损伤（其引发的情况与癌症发展的初始阶段相同）会引发与有丝分裂异常相关的四倍体/非整倍体产生。尽管癌基因加速主要在S期诱导DNA复制应激以及由此产生的损伤，但这些损伤会延续到M期，并导致胞质分裂失败和基因组不稳定性。与直接诱导的DNA双链断裂不同，与DNA复制应激相关的损伤是隐匿性的，并且由于检查点因子的有限且无效激活而能通过细胞周期检查点。此外，由于受损的M期细胞仍然会进行有丝分裂步骤，这些细胞会导致染色体错误分离、胞质分裂失败以及由此产生的四倍体形成。因此，我们的结果揭示了由癌前DNA复制应激引发的基因组不稳定性产生的过程。