Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint

• DOI: 10.1016/j.celrep.2025.115323
• Publication Date: 2025-02-16T00:31:03Z
• Authors: Francesca Macaluso; Tasia Bos; Elena Chiroli; Paolo Bonaiuti; Jason C. Apuan; Fridolin Gross; Simone Pompei; Luke M. Rice; Andrea Ciliberto
• Keywords: Spindle checkpoint

Microtubules are polymers required for chromosome segregation. Their drug-induced hyperstabilization impairs segregation and is an established anti-cancer therapy. How cells respond to microtubule hyperstabilization, however, incompletely understood. To study this, we evolved budding yeast expressing a microtubule-hyperstabilizing tubulin mutant isolated adapted strains. Aneuploidy of specific chromosomes carrying the regulators STU2 VIK1/KAR3 was first observable adaptation. In longer run, aneuploidies were outcompeted by mutations in α- or β-tubulin, partially overlapping with cancer patients. Thus, compensation follows restrained reproducible path where new combine original offending mutation on same carrier. While partly compensatory, several failed re-establish fully normal dynamics. Sustained growth relied mitotic checkpoint, indicating that extended timing limits genomic instability caused reduced Our results predict potential vulnerability resistant agents.