Genetic instability from a single S phase after whole-genome duplication - Université de Versailles Saint-Quentin-en-Yvelines Access content directly
Journal Articles Nature Year : 2022

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

Simon Gemble
René Wardenaar
Kristina Keuper
Nishit Srivastava
Maddalena Nano
  • Function : Author
Anne-Sophie Macé
Andréa Tijhuis
  • Function : Author
Sara Vanessa Bernhard
  • Function : Author
Diana Spierings
Anthony Simon
  • Function : Author
Oumou Goundiam
  • Function : Author
Helfrid Hochegger
  • Function : Author
Matthieu Piel
Floris Foijer
Zuzana Storchová
Renata Basto


Abstract 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 and DNA double-strand breaks 10 . 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.
Fichier principal
Vignette du fichier
s41586-022-04578-4.pdf (12.27 Mo) Télécharger le fichier
Origin Publisher files allowed on an open archive

Dates and versions

hal-03857401 , version 1 (26-11-2022)



Simon Gemble, René Wardenaar, Kristina Keuper, Nishit Srivastava, Maddalena Nano, et al.. Genetic instability from a single S phase after whole-genome duplication. Nature, 2022, 604 (7904), pp.146-151. ⟨10.1038/s41586-022-04578-4⟩. ⟨hal-03857401⟩
15 View
27 Download



Gmail Mastodon Facebook X LinkedIn More