Department of Pathological Biochemistry, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
PLoS One. 2010 Jan 21;5(1):e8821. doi: 10.1371/journal.pone.0008821.
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，细胞获得了与基因组不稳定性发展相关的永生性。然而，基因组不稳定性如何在肿瘤发生过程中自发产生仍然难以捉摸。在这里，我们表明，致癌基因加速诱导的癌前 DNA 损伤，诱导与癌症发展初始阶段相同的情况，与有丝分裂异常一起引发四倍体/非整倍体的产生。虽然致癌基因加速主要诱导 S 期的 DNA 复制应激和由此产生的损伤，但这些损伤会延续到 M 期，并导致细胞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，由于检查点因子的有限和无效激活，与 DNA 复制应激相关的损伤是隐源性的，并通过细胞周期检查点。此外，由于受损的 M 期细胞仍在有丝分裂步骤中进展，这些细胞导致染色体错误分离、细胞分裂失败和随后的四倍体产生。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过程。
