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

Area of Science:

• Cell Biology
• Genetics
• Cancer Research

Background:

• Microtubules are essential for chromosome segregation during cell division.
• Drug-induced microtubule hyperstabilization is a cancer therapy that impairs chromosome segregation.
• Cellular responses to microtubule hyperstabilization are not fully understood.

Purpose of the Study:

• To investigate cellular adaptation mechanisms to microtubule hyperstabilization.
• To identify genetic changes that confer resistance to microtubule-stabilizing agents.

Main Methods:

• Evolved budding yeast strains with a microtubule-hyperstabilizing tubulin mutant.
• Isolated and analyzed adapted strains for genetic and chromosomal alterations.
• Sequenced tubulin genes and assessed chromosome content.

Main Results:

• Initial adaptation involved aneuploidy of chromosomes carrying microtubule regulators (STU2, VIK1/KAR3).
• Longer-term adaptation occurred through mutations in alpha- or beta-tubulin, some overlapping with cancer mutations.
• Mutations partially compensated for hyperstabilization but often failed to restore normal microtubule dynamics.
• Sustained growth depended on the mitotic checkpoint, suggesting extended mitotic timing mitigates genomic instability.

Conclusions:

• Cellular adaptation to microtubule hyperstabilization follows a defined evolutionary path involving aneuploidy and specific tubulin mutations.
• These adaptations, while partly compensatory, can lead to reliance on the mitotic checkpoint.
• The findings predict a potential vulnerability in cancer cells resistant to microtubule-targeting therapies.