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 FachinettiYlli Doksani, Stefano Santaguida*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish
Article number1353
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

Funding

FundersFunder number
Fondazione IEO-Monzino
Centre National de la Recherche Scientifique
Fondazione Cariplo
European Molecular Biology Organization
Israel Cancer Research Fund
Ministero dell’Istruzione, dell’Università e della Ricerca
European Research Council
DoD CDMRP191148
Horizon 2020 Framework Programme945674
Ministero della Salute5 × 1000
Israel Science Foundation1805/21
Associazione Italiana per la Ricerca sul Cancro21665, 26738-2021, GR-2018-12367077

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