DNA Lesions Induced by Replication Stress Trigger Mitotic Aberration and Tetraploidy Development

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