Mild replication stress causes aneuploidy by deregulating microtubule dynamics in mitosis

Area of Science:

• Cancer Biology
• Cell Biology
• Genetics

Background:

• Chromosomal instability (CIN) is a hallmark of cancer, characterized by chromosome aberrations.
• Replication stress (RS) drives structural aberrations, while mitotic defects cause aneuploidy.
• The link between RS and chromosome segregation in CIN cancer cells is poorly understood.

Purpose of the Study:

• To elucidate the mechanisms by which replication stress influences chromosome segregation in chromosomally unstable cancer cells.
• To investigate the role of mild replication stress in driving aneuploidy and its impact on mitotic processes.

Main Methods:

• Utilized cancer cell models exhibiting chromosomal instability.
• Induced mild replication stress using low-dose aphidicolin treatment.
• Analyzed chromosome missegregation during mitosis and microtubule dynamics.

Main Results:

• Very mild replication stress, both endogenous and induced, leads to chromosome missegregation and aneuploidy.
• Replication stress increases microtubule plus end growth rates during mitosis.
• RS-induced chromosome missegregation is dependent on elevated microtubule growth rates.

Conclusions:

• Mild, cancer-relevant replication stress triggers aneuploidy by deregulating microtubule dynamics in mitosis.
• Targeting replication stress or restoring normal microtubule dynamics may offer therapeutic strategies for CIN cancers.