Investigating cell cycle vulnerabilities in TP53 mutant cancers

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Normally when a cell divides it creates a perfect copy of itself, including its copy of the genome through a process called cell division that physically separates the cell and its contents into two halves that become two new, genetically identical cells. This process must be precise and so is stringently controlled. One way the cell makes sure that cell division occurs without errors is the presence of checkpoints - these are places that the cell pauses in the division cycle to ensure that no mistakes have been made. Any mistakes that occur in the precise separation of the two new genomes can lead to dramatic and potentially cancer-causing genetic mutations, or cell death. One common mutation in many different types of cancer occurs in the gene for p53, also known as 'the guardian of the genome' because it is so important in protecting the cell from mistakes during cell division. If p53, or other genes that are associated with p53 to do its job are mutated, some cell cycle checkpoints no longer work, meaning that the cell can now continue dividing even though it has mistakes. We discovered that a cell cycle checkpoint that is supposed to make sure that the DNA gets untangled before it separates into the two new cells doesn't function if p53 is mutated, so some cancer cells aren't very good at untangling their DNA.Cancer cells have evolved to have a back-up pathway to be able to deal with this. They are forced to trigger a 'failsafe' set of proteins to get the job of untangling the DNA done so that each new cell gets an equal copy of the genome. We now require new knowledge in order to understand why mutation of p53 leads to loss of the DNA detangling surveillance checkpoint and what are the exact failsafe proteins involved in the back-up pathway. Once we learn this we want to translate this finding into a new therapy for cancer. We have discovered a new way to kill cancer cells using drugs that target these failsafe proteins. Since the failsafe proteins are only needed by cancer cells, these drugs will therefore leave the normal, healthy cells alone, meaning less side effects for the patients.