A lethal mutation is one that spells certain death for an organism. These mutations can be induced by a researcher, or occur spontaneously between generations. Sometimes, a mutation isn’t lethal unless it is combined with another nonlethal mutation – a condition called synthetic lethality. This kind of interaction is important because it can cause a daughter cell to die unexpectedly. One example of this kind of interaction is a mutation in the BRCA1 or BRCA2 gene and a mutation in the Poly-ADP Ribose Polymerase (PARP) gene, leading to a loss of function. Independently, mutations in either one of these genes would not cause cell death. However, when both genes are mutated, a synthetic lethal interaction occurs, and the cells can die. Additionally, mutations do not have to occur for a synthetic lethal interaction to occur. If the action of PARP is inhibited (for example, by a small molecule), it is possible that the synthetic lethal result can still occur.
This type of interaction can be taken advantage of when cell death is desired, namely, cancer cell death. Scientists have observed that most cancer cells have mutations in cohesin related genes, which are genes that create proteins that oversee how chromosomes separate during cell replication.
The goal of a study by Jessica McLellen et. al. was to see if PARP inhibitors could lead to cell death in cancerous cells with mutations in their cohesin related genes. They approached this by looking at model organisms representative of human systems, namely yeast (Saccharomyces cerevisiae) and a nematode worm (Caenorhabditis elegans). These organisms have very similar replication systems, and as the authors hypothesized, would be representative of how human systems work. The authors looked for, and found, processes that were required for survival after cohesin mutations in yeast. They then checked for these same systems in C. elegans. They hypothesized that if these systems are conserved between the two species, they are probably conserved in humans as well. Using this information, the authors found that when cohesin is mutated, several proteins related to replication fork progress and stability were required. This lead them to hypothesize that proteins not found in yeast but found in C. elegans would be required for other higher eukaryotes. These proteins included the aforementioned PARP. After testing human cells, the authors found that cells with cohesin mutations were less likely to survive when treated with a PARP inhibitor. This is significant because cancerous cells are the ones that likely have cohesin mutations, and those ones can be made less viable by treatment with PARP inhibitors.
Cancer treatments that target PARP inhibition are already on the way and are in phase II of clinical trials. This research supports their effectiveness with evidence from model organisms that have very similar systems when compared with humans. While the exact mechanism that contributes to the lethality is not yet fully understood, this work shows that PARP inhibition is a viable target for tumors with cohesin mutations, which represents a significant percentage of colorectal, ovarian, and breast cancers.
McLellan JL, O’Neil NJ, Barrett I, Ferree E, van Pel DM, et al. (2012) Synthetic Lethality of Cohesins with PARPs and Replication Fork Mediators. PLoS Genet 8(3): e1002574. doi:10.1371/journal.pgen.1002574