Final Report Summary - KINSIGN (Guarding Genome Stability: Dynamic Control of Chromosome Segregation by Kinetochore Signalling Pathways)
Error-free chromosome segregation is essential for all life. This ERC-StG project aimed to gain molecular mechanistic understanding of how this process is regulated in space and time. Key to chromosome segregation are the kinetochores; large multiprotein assemblies that are responsible for connecting chromosomes to the spindle microtubules that are responsible for pushing and pulling the chromosomes in the right direction during cell division. When bad connections are made, error-correction mechanisms ensure that they are converted to proper connections. During such error-correction, cell division is halted by a checkpoint that will only allow division if all chromosomes are connected correctly. Both the error-correction and the checkpoint mechanisms reside at the kinetochore and monitor the state of chromosome spindle attachment. With the ERC grant, we wished to understand how these mechanisms work. We discovered that they are in fact connected: the error-correction mechanisms ensures activity of the checkpoint and vice versa. We further revealed how they are connected: both mechanisms share a requirement for the same set of crucial enzymes known as kinases. They are known bu the names Aurora B, Mps1 and Bub1. We discovered how some of these kinases are able to be located at kinetochores, and what controls that localization. For instance, we showed that Mps1 needs Aurora B activity to bind a partiular protein complex known as the Ndc80 complex at kinetochores. We further discovered how the kinases, once located to the right location, achieve their goals, i.e. error-correction and cell division arrest. For instance, we showed that Mps1 activity chemically modifies a scaffold protein on multiple sites to create a docking site for a regulator of chromosome segregation. We also showed that there are important roles for the anti-kinases, known as phosphatases, in the signaling networks and we defined at least some of those roles in molecular detail. For instance, we showed that cell division arrest imposed by the kinases can only be lifted when these phosphatases are able to visit kinetochores at the right moment.
Our findings will contribute to understanding how mistakes in chromosome segregation are prevented so as to ensure development of healthy organisms. Moreover, since cancer cells have long been known to make frequent errors in this process, we hope to contribute to understanding what aspect of the molecular controls of chromosome segregation are defective in cancer cells. Related to this, in a separate set of experiments, we sought to determine in what ways errors in chromosome contribute to genomic chaos in cancer cells. We found that various long-known genomic alterations in cancer cells (known as chromosomal translocations) can be directly caused by these cell division errors. Finally, since we have previously shown that the frequent errors in chromosome segregation are a weak point in the armour of cancer cells, our insights into how the control networks operate may lead to better ways to inhibit those networks in cancer cells and set them up for catastrophic cell divisions.
Our findings will contribute to understanding how mistakes in chromosome segregation are prevented so as to ensure development of healthy organisms. Moreover, since cancer cells have long been known to make frequent errors in this process, we hope to contribute to understanding what aspect of the molecular controls of chromosome segregation are defective in cancer cells. Related to this, in a separate set of experiments, we sought to determine in what ways errors in chromosome contribute to genomic chaos in cancer cells. We found that various long-known genomic alterations in cancer cells (known as chromosomal translocations) can be directly caused by these cell division errors. Finally, since we have previously shown that the frequent errors in chromosome segregation are a weak point in the armour of cancer cells, our insights into how the control networks operate may lead to better ways to inhibit those networks in cancer cells and set them up for catastrophic cell divisions.