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

Nom de la revue
Simon Gemble, René Wardenaar, Kristina Keuper, Nishit Srivastava, Maddalena Nano, Anne-Sophie Macé, Andréa E. Tijhuis, Sara Vanessa Bernhard, Diana C. J. Spierings, Anthony Simon, Oumou Goundiam, Helfrid Hochegger, Matthieu Piel, Floris Foijer, Zuzana Storchová, Renata Basto

AbstractDiploid 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 cancers1–3. It has been established that whole-genome duplications fuel chromosome instability through abnormal mitosis4–8; 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 tumorigenesis9 and DNA double-strand breaks10. 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.