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

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 and Renata Basto ()
Additional contact information
Simon Gemble: Institut Curie, PSL Research University, CNRS, UMR144, Biology of Centrosomes and Genetic Instability Laboratory
René Wardenaar: University of Groningen, University Medical Center Groningen
Kristina Keuper: TU Kaiserslautern
Nishit Srivastava: PSL Research University, CNRS, UMR 144, Systems Biology of Cell Polarity and Cell Division
Maddalena Nano: Institut Curie, PSL Research University, CNRS, UMR144, Biology of Centrosomes and Genetic Instability Laboratory
Anne-Sophie Macé: Institut Curie, PSL Research University, Centre National de la Recherche Scientifique
Andréa E. Tijhuis: University of Groningen, University Medical Center Groningen
Sara Vanessa Bernhard: TU Kaiserslautern
Diana C. J. Spierings: University of Groningen, University Medical Center Groningen
Anthony Simon: Institut Curie, PSL Research University, CNRS, UMR144, Biology of Centrosomes and Genetic Instability Laboratory
Oumou Goundiam: Institut Curie, PSL Research University, CNRS, UMR144, Biology of Centrosomes and Genetic Instability Laboratory
Helfrid Hochegger: University of Sussex
Matthieu Piel: PSL Research University, CNRS, UMR 144, Systems Biology of Cell Polarity and Cell Division
Floris Foijer: University of Groningen, University Medical Center Groningen
Zuzana Storchová: TU Kaiserslautern
Renata Basto: Institut Curie, PSL Research University, CNRS, UMR144, Biology of Centrosomes and Genetic Instability Laboratory

Nature, 2022, vol. 604, issue 7904, 146-151

Abstract: 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 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.

Date: 2022
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DOI: 10.1038/s41586-022-04578-4

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