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, Renata Basto*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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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). 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.

Original languageEnglish
Pages (from-to)146–151
Number of pages29
JournalNature
Volume604
Early online date30-Mar-2022
DOIs
Publication statusPublished - Apr-2022

Keywords

  • DNA-REPLICATION
  • CYCLE
  • CYTOKINESIS
  • TRANSCRIPTION
  • POLYPLOIDY
  • EXPRESSION
  • DYNAMICS
  • E2F
  • G1

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