Loss of the tumour suppressor transcription factor p53 is associated with replication stress and genome instability, two preconditions for tumorigenesis. Chromothripsis is an extreme form of genome instability characterized by massive chromosomal rearrangements, and a well-known driver of tumorigenesis linked to p53 loss. How p53 loss causes chromothripsis is unclear. Now, a study by Zaatra et al. determines the sequence of events triggered by p53 loss that leads to chromothripsis.
The authors hypothesized that the TP53 mutations in LFS cells cause replication stress. DNA combing experiments showed that early-passage LFS cells experienced replication stress, which was exacerbated during crisis and coincided with loss of wild-type p53, suggesting a causative relationship between p53 loss of function, replication stress and chromothripsis. Importantly, late-passage LFS cells, which escaped the crisis, had normal replication rates.
