Abstract
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.
Highlights
Genomic instability is observed in most cancer cells [1]
To test the above hypothesis (Supplementary Fig. S1), we initiated a study of DNA lesions induced by oncogenes, such as E2F1, because the initial stages of cancer development are mimicked by oncogene-acceleration, in which genomic instability is subsequently developed [2]
Our results showed one of the processes in developing genomic instability by precancerous DNA lesions, in which the lesions are carried over into the M phase and cause chromosomal mis-segregation and cytokinesis failure, resulting in tetraploidy generation
Summary
In the earliest stages of cancer development, cells exhibit DNA lesions, which are characterized as precancerous DNA lesions and are induced by DNA replication stress with the accelerated cell cycle progression as the results of oncogene acceleration or of aberrant growth activation [2,3] During these stages, anti-cancer barrier reactions including cell cycle arrest and inductions of senescence and apoptosis are competitively activated to block the tumorigenesis step progression [2,3], genomic instability is subsequently started to appear prior to the development of cancer [2,3]. Consistent with the hypothesis of aneuploidy development via unstable tetraploidy intermediates, cancer cells with chromosomal instability show the characteristics of continuous alteration in chromosomal status, highlighting the question for the initiation and the induction of tetraploidy
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