Preserving genome integrity during cell division requires regulated interactions between chromosomes

Preserving genome integrity during cell division requires regulated interactions between chromosomes and spindle microtubules. the kinetochore are linked to biochemical changes to control chromosome segregation. We discuss models for tension sensing and regulation of kinetochore function downstream of Aurora B and mechanisms that specify Aurora B localization to the inner centromere and determine its interactions with substrates at VX-222 unique locations. Introduction The accurate segregation of chromosomes during cell division is essential to maintain genomic stability. In eukaryotic cells the microtubule-based mitotic spindle generates causes to align the sister chromatids in the metaphase plate and then to pull the sister chromatids in reverse directions to segregate them to the two child cells. VX-222 The kinetochore assembles in the centromere of each chromosome to mediate relationships with spindle microtubules. Kinetochores can in the beginning bind to microtubules in any construction but accurate chromosome segregation requires that every pair of sister kinetochores ultimately attach to microtubules from reverse spindle poles (bi-orientation). Although there is a bias towards bi-orientation due to geometric constraints imposed by chromosome structure [1 2 frequent errors in kinetochore-microtubule attachments do happen [3 4 and would lead VX-222 to unequal segregation if remaining uncorrected. Consequently kinetochore-microtubule Rabbit Polyclonal to AKR1A1. attachments must be cautiously regulated: incorrect attachments are destabilized while right attachments are stabilized. In this way all kinetochores eventually reach the correct attachment state inside a trial-and-error process with destabilization providing a fresh opportunity to bi-orient (examined in [5]). Defining the mechanism that selectively stabilizes only correct attachments is critical to understanding appropriate chromosome segregation. Here we review recent work to understand the molecular mechanisms by which erroneous attachments are recognized and corrected focusing on the part of Aurora B kinase in this process. We discuss the processes that take action upstream to control the activity of Aurora B and its phosphorylation of kinetochore substrates and the downstream effects of Aurora B phosphorylation for kinetochore activity and function. Regulating attachments: reconciling mechanical and molecular mechanisms Classic experiments by Bruce Nicklas using micromanipulation in insect spermatocyes offered direct experimental evidence that attachments are stabilized through pressure VX-222 across the centromere. In cells this pressure is made as spindle microtubules pull bi-oriented kinetochores in reverse directions. Experimentally induced pressure applied having a glass microneedle stabilizes unipolar attachments that are normally unstable [6 7 These experiments laid the foundation for any model to explain the general basic principle of how bi-orientation can be achieved before any molecular details of this rules had been defined. One of the 1st pieces to the molecular puzzle of tension-dependent rules was the recognition of the Ipl1 kinase in budding candida in a display for mutants that display an increase-in-ploidy (ipl) phenotype [8]. Ipl1 was consequently shown to be required for accurate chromosome segregation and to phosphorylate kinetochore substrates regulating microtubule binding [9-11]. Furthermore Ipl1 promotes the turnover of attachments in the absence of pressure [12] suggesting that it might function in the pathway explained by Nicklas. Parallel work in components [58] although a similarly strong effect is not observed in human being cells [39]. In addition Aurora B and the CPC are required to recruit Shugoshin family proteins to VX-222 centromeres [59-64]. In contrast VX-222 Aurora B-dependent phosphorylation of outer kinetochore substrates could act as a switch to control kinetochore composition. Perhaps the best understood example of controlled kinetochore localization downstream of Aurora B is definitely Protein Phosphatase 1 (PP1) which localizes to kinetochores and opposes Aurora B (examined in [65]). A major PP1 targeting element at kinetochores is the outer kinetochore protein KNL1.