Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint
Summary: Microtubules are polymers required for chromosome segregation. Their drug-induced hyperstabilization impairs chromosome segregation and is an established anti-cancer therapy. How cells respond to microtubule hyperstabilization, however, is incompletely understood. To study this, we evolved...
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Elsevier
2025-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000944 |
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| author | Francesca Macaluso Tasia Bos Elena Chiroli Paolo Bonaiuti Jason C. Apuan Fridolin Gross Simone Pompei Luke M. Rice Andrea Ciliberto |
| author_facet | Francesca Macaluso Tasia Bos Elena Chiroli Paolo Bonaiuti Jason C. Apuan Fridolin Gross Simone Pompei Luke M. Rice Andrea Ciliberto |
| author_sort | Francesca Macaluso |
| collection | DOAJ |
| description | Summary: Microtubules are polymers required for chromosome segregation. Their drug-induced hyperstabilization impairs chromosome segregation and is an established anti-cancer therapy. How cells respond to microtubule hyperstabilization, however, is incompletely understood. To study this, we evolved budding yeast cells expressing a microtubule-hyperstabilizing tubulin mutant and isolated adapted strains. Aneuploidy of specific chromosomes carrying the microtubule regulators STU2 and VIK1/KAR3 was the first observable adaptation. In the longer run, aneuploidies were outcompeted by mutations in α- or β-tubulin, partially overlapping with mutations in cancer patients. Thus, compensation of microtubule hyperstabilization follows a restrained and reproducible path where new mutations combine with the original offending mutation on the same carrier. While partly compensatory, several mutations failed to re-establish fully normal microtubule dynamics. Sustained growth relied on the mitotic checkpoint, indicating that extended mitotic timing limits the genomic instability caused by reduced microtubule dynamics. Our results predict a potential vulnerability of cells resistant to microtubule-hyperstabilizing agents. |
| format | Article |
| id | doaj-art-d75d9ec3e6f344e28ea275e9d7868b1e |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-d75d9ec3e6f344e28ea275e9d7868b1e2025-08-20T02:48:23ZengElsevierCell Reports2211-12472025-02-0144211532310.1016/j.celrep.2025.115323Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpointFrancesca Macaluso0Tasia Bos1Elena Chiroli2Paolo Bonaiuti3Jason C. Apuan4Fridolin Gross5Simone Pompei6Luke M. Rice7Andrea Ciliberto8IFOM-ETS, The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, ItalyDepartments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USAIFOM-ETS, The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, ItalyIFOM-ETS, The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, ItalyDepartments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USAImmunoConcEpT, CNRS UMR5164, Université de Bordeaux, 33076 Bordeaux, FranceIFOM-ETS, The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, ItalyDepartments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USAIFOM-ETS, The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, 1083 Budapest, Hungary; Corresponding authorSummary: Microtubules are polymers required for chromosome segregation. Their drug-induced hyperstabilization impairs chromosome segregation and is an established anti-cancer therapy. How cells respond to microtubule hyperstabilization, however, is incompletely understood. To study this, we evolved budding yeast cells expressing a microtubule-hyperstabilizing tubulin mutant and isolated adapted strains. Aneuploidy of specific chromosomes carrying the microtubule regulators STU2 and VIK1/KAR3 was the first observable adaptation. In the longer run, aneuploidies were outcompeted by mutations in α- or β-tubulin, partially overlapping with mutations in cancer patients. Thus, compensation of microtubule hyperstabilization follows a restrained and reproducible path where new mutations combine with the original offending mutation on the same carrier. While partly compensatory, several mutations failed to re-establish fully normal microtubule dynamics. Sustained growth relied on the mitotic checkpoint, indicating that extended mitotic timing limits the genomic instability caused by reduced microtubule dynamics. Our results predict a potential vulnerability of cells resistant to microtubule-hyperstabilizing agents.http://www.sciencedirect.com/science/article/pii/S2211124725000944CP: Cell biology |
| spellingShingle | Francesca Macaluso Tasia Bos Elena Chiroli Paolo Bonaiuti Jason C. Apuan Fridolin Gross Simone Pompei Luke M. Rice Andrea Ciliberto Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint Cell Reports CP: Cell biology |
| title | Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint |
| title_full | Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint |
| title_fullStr | Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint |
| title_full_unstemmed | Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint |
| title_short | Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint |
| title_sort | evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint |
| topic | CP: Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725000944 |
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