Cohesin fatigue describes our findings that cells delayed at metaphase undergo asynchronous separation of chromatids. We found that these unpaired chromatids randomly migrate on spindle microtubules or become merotelic, wherein a single centromere attaches to spindle fibers from both poles. Many cells eventually exit mitosis after cohesion fatigue, and the unpaired chromatids can form micronuclei, can rupture, and can mis-segregate. These results suggest that cohesion fatigue may cause gain or loss of whole chromosomes (numerical aneuploidy) as well as duplications, deletions, or translocations of large chromosome fragments (segmental aneuploidy). Numerical and segmental aneuploidies are hallmarks of cancer cells, often occurring together, and cohesion fatigue is a potential mechanism for simultaneously generating both. Any induced metaphase delay will lead to cohesion fatigue as long as spindle function is intact. Among mitotic defects, cohesion fatigue may be relatively common, but has often gone unrecognized since its detection requires continuous tracking of chromosome behavior. We have observed that cohesion fatigue is induced after metaphase arrest caused by RNAi-mediated depletion of the Ska (Spindle and kinetochore-associated) complex. Recently we discovered the underlying mechanism for the metaphase delay in Ska-depleted cells. We find that the Ska complex promotes chromosome binding and activity of the Anaphase-Promoting Complex/Cyclosome, the E3 ubiquitin ligase that controls anaphase onset and mitotic exit. Cohesion fatigue is also induced by certain drugs such as proteasome inhibitors, which are under development for cancer therapy. Using proteasome inhibition we found that cohesion fatigue initiates at centromeres and progresses along chromosome arms. While complete chromatid separation may occur after hours of metaphase arrest, our recent tracking reveals that abnormal centromere separation occurs after a few minutes of arrest. This early loss of centromere cohesion may lead to mitotic defects in cells that experience even a brief metaphase delay. Cohesion fatigue is not observed in cells arrested in mitosis with microtubule poisons because outward pulling forces on chromosomes are lost. In normal dividing cells, spontaneous mitotic defects are relatively rare, but these are substantially increased in transformed cells. Genes coding for components and regulators of the cohesin complex, which mediates sister chromatid cohesion, are among the most highly mutated genes in tumors. We propose that cohesin defects in cancer cells may exacerbate cohesion fatigue leading to increased chromosome instability. In carcinogenesis, cells that undergo metaphase delays are likely to generate mitotic errors through cohesion fatigue that result in numerical and segmental aneuploidy.

Citation Format: John R. Daum, Sushama Sivakumar, Aaron R. Tipton, Michael W. Davidson, Gary J. Gorbsky. Metaphase delays lead to chromosome cohesion fatigue, a novel mechanism underlying chromosome instability and aneuploidy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5083. doi:10.1158/1538-7445.AM2014-5083