Genetic instability from a single S phase after whole-genome duplication

Diploid and stable karyotypes are associated with health and fitness in animals. By contrast, whole-genome duplications-doublings of the entire complement of chromosomes-are linked to genetic instability and frequently found in human cancers(1-3). It has been established that whole-genome duplications fuel chromosome instability through abnormal mitosis(4-8); however, the immediate consequences of tetraploidy in the first interphase are not known. This is a key question because single whole-genome duplication events such as cytokinesis failure can promote tumorigenesis(9). Here we find that human cells undergo high rates of DNA damage during DNA replication in the first S phase following induction of tetraploidy. Using DNA combing and single-cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we find that these defects result from a shortage of proteins during the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the genetic instability landscape that favours tumorigenesis after tetraploidization.

Automated summary

This study reveals that human cells experience high levels of DNA damage during DNA replication in the first S phase following tetraploidy induction. These damages are caused by protein shortage during the G1/S transition, resulting in inaccurate DNA replication. These findings provide an explanation for the genetic instability landscape that favors tumorigenesis after tetraploidization.