TY - JOUR
T1 - Short-term molecular consequences of chromosome mis-segregation for genome stability
AU - Garribba, Lorenza
AU - De Feudis, Giuseppina
AU - Martis, Valentino
AU - Galli, Martina
AU - Dumont, Marie
AU - Eliezer, Yonatan
AU - Wardenaar, René
AU - Ippolito, Marica Rosaria
AU - Iyer, Divya Ramalingam
AU - Tijhuis, Andréa E.
AU - Spierings, Diana C.J.
AU - Schubert, Michael
AU - Taglietti, Silvia
AU - Soriani, Chiara
AU - Gemble, Simon
AU - Basto, Renata
AU - Rhind, Nick
AU - Foijer, Floris
AU - Ben-David, Uri
AU - Fachinetti, Daniele
AU - Doksani, Ylli
AU - Santaguida, Stefano
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85150179760&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-37095-7
DO - 10.1038/s41467-023-37095-7
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C2 - 36906648
AN - SCOPUS:85150179760
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1353
ER -