Abstract
Accurate chromosome segregation during cell division is essential to maintain genome integrity in all eukaryotic cells, and chromosome missegregation leads to aneuploidy and therefore represents a hallmark of many cancers. Accurate segregation requires sister kinetochores to attach to microtubules emanating from opposite spindle poles, known as bipolar attachment or biorientation. Recent studies have uncovered several mechanisms critical to chromosome bipolar attachment. First, a mechanism exists to ensure that the conformation of sister centromeres is biased toward bipolar attachment. Second, the phosphorylation of some kinetochore proteins destabilizes kinetochore attachment to facilitate error correction, but a protein phosphatase reverses this phosphorylation. Moreover, the activity of the spindle assembly checkpoint is regulated by kinases and phosphatases at the kinetochore, and this checkpoint prevents anaphase entry in response to faulty kinetochore attachment. The fine-tuned kinase/phosphatase balance at kinetochores is crucial for faithful chromosome segregation during both mitosis and meiosis. Here, we discuss the function and regulation of protein phosphatases in the establishment of chromosome bipolar attachment with a focus on the model organism budding yeast.
Highlights
In mitosis, chromosome segregation occurs in a way that each daughter cell receives one copy of every chromosome
In budding yeast, the Bub1-H2A-Sgo1-PP2ARts1 axis prevents spindle assembly checkpoint (SAC) silencing prior to chromosome bipolar attachment [100]. These results suggest that PP2ARts1 promotes chromosome bipolar attachment by ensuring the correct conformation of pericentric chromatin and by preventing anaphase onset prior to chromosome biorientation and tension generation
The establishment of bipolar attachment is key to faithful chromosome segregation during mitosis
Summary
Chromosome segregation occurs in a way that each daughter cell receives one copy of every chromosome. Phosphorylation of some kinetochore substrates by a conserved kinase Aurora B (Ipl in budding yeast) destabilizes KT-MT interaction to facilitate error correction This phosphorylation is reversed by increasing phosphatase activity at kinetochores to stabilize the KT-MT interaction [4]. Tightly regulated protein phosphatase activity at kinetochores is critical to accurate chromosome segregation during meiosis If any of these mechanisms fail, the consequence is chromosome missegregation or aneuploidy, which is a hallmark of cancer cells and is the cause for genetic disorders like Down syndrome (Trisomy 21). The regulation of simultaneous kinase and phosphatase activity at the kinetochore remains one of the most important yet elusive undertakings Further unveiling of these detailed mechanisms will elucidate additional key players in chromosome bipolar attachment and prove beneficial for cancer drug development. We discuss the antagonistic relationships between kinases and phosphatases and their roles in promoting accurate chromosome segregation, with a focus on budding yeast Saccharomyces cerevisiae
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