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

Author

Listed:
  • 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
    University of California)

  • 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)

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.

Suggested Citation

  • 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 Goun, 2022. "Genetic instability from a single S phase after whole-genome duplication," Nature, Nature, vol. 604(7904), pages 146-151, April.
  • Handle: RePEc:nat:nature:v:604:y:2022:i:7904:d:10.1038_s41586-022-04578-4
    DOI: 10.1038/s41586-022-04578-4
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    Citations

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    Cited by:

    1. Lorenza Garribba & Giuseppina De Feudis & Valentino Martis & Martina Galli & Marie Dumont & Yonatan Eliezer & René Wardenaar & Marica Rosaria Ippolito & Divya Ramalingam Iyer & Andréa E. Tijhuis & Dia, 2023. "Short-term molecular consequences of chromosome mis-segregation for genome stability," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Dadong Dai & Chuanshuai Xie & Yayi Zhou & Dexin Bo & Shurong Zhang & Shengqiang Mao & Yucheng Liao & Simeng Cui & Zhaolu Zhu & Xueyu Wang & Fanling Li & Donghai Peng & Jinshui Zheng & Ming Sun, 2023. "Unzipped chromosome-level genomes reveal allopolyploid nematode origin pattern as unreduced gamete hybridization," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. G. Yahya & P. Menges & P. S. Amponsah & D. A. Ngandiri & D. Schulz & A. Wallek & N. Kulak & M. Mann & P. Cramer & V. Savage & M. Räschle & Z. Storchova, 2022. "Sublinear scaling of the cellular proteome with ploidy," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Adam C. Weiner & Marc J. Williams & Hongyu Shi & Ignacio Vázquez-García & Sohrab Salehi & Nicole Rusk & Samuel Aparicio & Sohrab P. Shah & Andrew McPherson, 2024. "Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Maritzaida Varela Salgado & Ingrid E. Adriaans & Sandra A. Touati & Sandy Ibanes & Joséphine Lai-Kee-Him & Aurélie Ancelin & Luca Cipelletti & Laura Picas & Simonetta Piatti, 2024. "Phosphorylation of the F-BAR protein Hof1 drives septin ring splitting in budding yeast," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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