Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function

Area of Science:

• Cell Biology
• Genetics
• Cancer Research

Background:

• Warsaw breakage syndrome (WABS) is linked to DDX11 DNA helicase defects, crucial for chromatid cohesion.
• Cohesion defects impair cell division and are implicated in various cancers.

Purpose of the Study:

• To investigate the sensitivity of WABS cells and other cohesion-defective cells to disruptions in cell cycle regulation.
• To identify potential therapeutic targets for cancers with cohesion defects.

Main Methods:

• Genome-wide siRNA screening in patient-derived WABS cell lines.
• Assessment of cell viability upon treatment with APC/C inhibitor (apcin) and paclitaxel.
• Analysis of mitotic spindle checkpoint function and microtubule dynamics.

Main Results:

• WABS cells are intolerant to partial depletion of APC/C subunits or p31(comet).
• Combined cohesion defects and impaired APC/C function induce lethal mitotic arrest.
• WABS and cancer cell lines with cohesion defects show heightened sensitivity to apcin, but not paclitaxel.
• Synthetic lethality is dependent on a functional spindle checkpoint and microtubule forces.

Conclusions:

• Cohesion defects combined with APC/C inhibition lead to synthetic lethality via cohesion fatigue and mitotic arrest.
• APC/C inhibitors represent a promising therapeutic strategy for targeting cohesion-defective cancers.