Short-term molecular consequences of chromosome mis-segregation for genome stability

Lorenza Garribba, Giuseppina De Feudis, Valentino Martis, Martina Galli, Marie Dumont, Yonatan Eliezer, René Wardenaar, Marica Rosaria Ippolito, Divya Ramalingam Iyer, Andréa E. Tijhuis, Diana C. J. Spierings, Michael Schubert, Silvia Taglietti, Chiara Soriani, Simon Gemble, Renata Basto, Nick Rhind, Floris Foijer, Uri Ben-David, Daniele Fachinetti, Ylli Doksani and Stefano Santaguida ()
Additional contact information
Lorenza Garribba: European Institute of Oncology IRCCS
Giuseppina De Feudis: European Institute of Oncology IRCCS
Valentino Martis: European Institute of Oncology IRCCS
Martina Galli: IFOM ETS - The AIRC Institute of Molecular Oncology
Marie Dumont: Institut Curie, PSL Research University, CNRS
Yonatan Eliezer: Tel Aviv University
René Wardenaar: University of Groningen, University Medical Center Groningen
Marica Rosaria Ippolito: European Institute of Oncology IRCCS
Divya Ramalingam Iyer: University of Massachusetts Chan Medical School
Andréa E. Tijhuis: University of Groningen, University Medical Center Groningen
Diana C. J. Spierings: University of Groningen, University Medical Center Groningen
Michael Schubert: University of Groningen, University Medical Center Groningen
Silvia Taglietti: European Institute of Oncology IRCCS
Chiara Soriani: European Institute of Oncology IRCCS
Simon Gemble: Institut Curie, PSL Research University, CNRS
Renata Basto: Institut Curie, PSL Research University, CNRS
Nick Rhind: University of Massachusetts Chan Medical School
Floris Foijer: University of Groningen, University Medical Center Groningen
Uri Ben-David: Tel Aviv University
Daniele Fachinetti: Institut Curie, PSL Research University, CNRS
Ylli Doksani: IFOM ETS - The AIRC Institute of Molecular Oncology
Stefano Santaguida: European Institute of Oncology IRCCS

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Chromosome instability (CIN) is the most common form of genome instability and is a hallmark of cancer. CIN invariably leads to aneuploidy, a state of karyotype imbalance. Here, we show that aneuploidy can also trigger CIN. We found that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN. This generates a repertoire of genetically diverse cells with structural chromosomal abnormalities that can either continue proliferating or stop dividing. Cycling aneuploid cells display lower karyotype complexity compared to the arrested ones and increased expression of DNA repair signatures. Interestingly, the same signatures are upregulated in highly-proliferative cancer cells, which might enable them to proliferate despite the disadvantage conferred by aneuploidy-induced CIN. Altogether, our study reveals the short-term origins of CIN following aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for aneuploidy occurrence in tumors.

Date: 2023
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DOI: 10.1038/s41467-023-37095-7

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