Galway research into the processes that allow a cell to make a perfect genetic copy of itself may aid the fight against cancer, writes Dick Ahlstrom
The two most important things a cell has to get right during its lifetime are the creation of daughter cells through division and the protection of the genetic code. Getting either of these crucial functions wrong can cause cell death, or worst still, lead to abnormal growth and cancer.
A research team at NUI Galway is delving into these two essential processes in a study based in the department of biochemistry. It involves a detailed analysis of what is going on during cell division or mitosis and when the cell carries out essential "maintenance" on its DNA, says Dr Ciaran Morrison, who leads the research team.
"The cell has two important things to do when trying to divide," says Morrison, who received five-year Science Foundation Ireland funding worth almost €1.5 million to conduct the work. It must copy its DNA, and then accurately deliver identical copies to both daughter cells during mitosis.
"We are trying to use genetics and cell biology to investigate the links between the mechanisms that control maintenance of the chromosomes and the mechanisms that maintain mitosis," Morrison says. These two systems are co-ordinated but it remains unclear how they are linked and how-or if-they talk to one another.
Progress in the analysis depends on interfering with the normal cellular processes to see what effect this has on mitosis and DNA repair. This is done by disrupting individual genes to create mutations, and then assessing the impact on cell biology. "The bulk of our work is with genes that have a role in these processes," says Morrison.
Radiation and chemical substances are used to cause breaks and errors in the DNA, but the best way to introduce mutations is by direct intervention, targeting an individual gene, he says. It is challenging work but you know exactly which gene has been disabled and so will have a better understanding of what contribution the gene makes to essential cell processes.
"We work on tumour cell lines for all our work," Morrison explains. "Most of the really important genes are essential so there is not a great deal of difference between tumour and normal cells."
They use "gene targeting" to tailor mutations into the gene of interest. This involves adding extra DNA, for example for antibiotic resistance, which is bracketed on either side by DNA segments that the cell can recognise. This "plasmid" gets incorporated into the gene, but causes it to stop functioning, to mutate or die.
When a gene has been knocked out or mutated, the team can assess the impact of this loss on mitosis or DNA repair by direct observation. "We can see these things down a microscope," states Morrison.
"We can see the DNA repair factors and see how they respond to damage." In effect they are looking at the "real time DNA repair capacity" of the cell.
The research team wants to understand the contribution made by various genes associated with mitosis and DNA repair, the reason being that failures in these essential cell functions can often become a trigger for the development of cancers.
Aberrant genes can cause inappropriate cell division and growth, so this work should lead to a better understanding of how cancers might occur and progress, says Morrison. It should also point towards ways to increase the efficacy of chemotherapy treatments that damage cancer cells.
Morrison's research effort is also looking at telomeres, the structures found at the end of a chromosome. These have a role in maintaining DNA integrity and gradually shorten over a person's lifetime. Telomere elements are also being knocked out "to see if it affects repair or mitosis", says Morrison.