Conservation of genome integrity by the NoCut pathway
In order to develop and repair all of the body tissues that living organisms are made from, each of the cells that make up the organism must be copied and divide into two new daughter cells many times. The genetic information contained within these cells is packaged chromosomes and these must also be very carefully coped during this life cycle. This is a very complicated process and requires a set of stringent quality controls that ensure that all genetic information is copied and distributed properly between the two daughter cells each time. These quality controls check that the replication of the genetic material, the DNA, is complete, that is it undamaged and finally that the two daughter copies of the chromosome are properly packaged and separated into the two daughter cells. This system is called the cell cycle and is essential for life.
We are interested in a final quality control, which checks that the replicated chromosomes are properly segregated into the two daughter cells before the daughter cells are permanently separated. This quality control point is called the NoCut Checkpoint and is an important control point as sometimes the migration of the two sister chromosomes to opposite daughter cells is incomplete or fails entirely. If the cell makes the final division once this mistake has been made, genetic information can be physically lost, damaged or mutated. It is very important for the organism that this does not happen as this type of damage can cause death of the individual cell and is also thought to be one of the contributing factors in development of cancer.
The aim of this project was to understand how the cell detects whether or not an error in segregation of the genetic information has been made, and therefore whether to activate the NoCut checkpoint. This is important because it may help us to understand how this mechanism is triggered and therefore give insights into if and why is may fail during cancer progression. This may therefore lead to clues about which parts of the process, if any it would be useful to target in future treatment strategies.
In order to achieve this we used yeast as a model system. Yeast is a very useful research tool as it allows us to easily and quickly make genetic changes to test hypotheses. We can then easily confirm the observations made in yeast cells in human cells to check that they are relevant to human cell biology. During this project, we have now identified 2 genes that are essential for the NoCut checkpoint to function. These genes code for proteins that physically bind to DNA and are able to detect changes in DNA structure due to damage and mistakes in DNA replication. We therefore think that these proteins could be the key to understanding the connection between mistakes in the replication and segregation of genetic material and the NoCut checkpoint. We have also confirmed that a highly related protein performs the same function in human cancer cells giving us a really important insight into how the cell is able to perform this type of error checking and therefore how this may function in cancer cells. The next step in this work will be to further map which other genes interact with this pathway and to use real patient cancer sample to test whether this pathway is functional in cancer cells.
