An NUI Galway team is studying a key system used by the body to repair damaged DNA and help prevent cancers. Dick Ahlstrom reports
Cells go to great lengths to protect the integrity of our genetic code. They use powerful systems that respond instantly whenever damage occurs to DNA, carrying out running repairs and even triggering spontaneous cell death if the damage is too great.
These systems are known collectively as the "DNA damage checkpoint pathway". The pathway co-ordinates a range of responses inside the cell when DNA is damaged by sunlight, chemicals or ionising radiation.
"This pathway is crucially important for the prevention of cancer," explains Prof Noel Lowndes of NUI Galway. The university is researching how the pathway works, and Lowndes is building a team to learn its secrets.
He returned to the Republic from the Imperial Cancer Research Fund in Britain, one of the top cancer research organisations in the world. He now heads the "Genome Stability Cluster", part of the National Centre for Biomedical Engineering Science at NUI Galway. The cluster received funding worth €2.7million from the university, from the PRTLI programme run by the Higher Education Authority and from the Health Research Board.
The cluster has five lead researchers including Dr Ciaran Morrison, who recently received an additional €1.4 million investigator award from Science Foundation Ireland. "What we are hoping to build here in Galway is a world-class centre for this subject," says Lowndes.
Our genetic code is under constant threat and assault, much of it - but not all - brought on by our own actions. Ultraviolet radiation from the sun can cause breaks in our DNA. Free oxygen from the foods we eat causes damage, as do cosmic rays from space and from natural and man-made radiation sources.
DNA is shaped like a ladder that has been twisted into a helix. The cell's own repair systems can fix single breaks in this ladder, but the pathway intervenes when a more serious, double-strand break occurs.
The pathway is a handful of very important proteins circulating in the nucleus, and ready to spring into action. "You can think of it as a panic response," says Lowndes. The proteins react immediately to the damage, triggering a cascade of events that can fix things in minutes or within a few hours.
"The biochemistry of the pathway is still largely unknown," he says. "My particular interest is at the very top of the pathway, how does it detect the damage?"
Once set in motion, the pathway has profound effects inside the cell. It can halt cell division for up to a day or two while repairs occur. It can increase the effectiveness of the repair systems by changing or increasing the output of repair proteins. And if a cell cannot be repaired, it triggers controlled cell death, apoptosis.
Interest in the pathway is strong because its failure can result in the development of cancers. Unrepaired damage can cause mutations in the DNA, errors that are carried into subsequent generations of a cell. The initiating "genome instability" can cause later mutations, and it is believed that at least six or seven such mutations are needed to convert a normal cell into a cancer cell, he says.
Normal cells divide with such accuracy that it would be virtually impossible for a single cell to accumulate all the necessary mutations needed to become cancerous. The pathway proteins ensure that cells which go wrong are either corrected or killed off.
The Galway team is looking however at what happens when the initial instability occurs in genes responsible for the protective pathway proteins. "Mutation of pathways that control genome stability has been shown to be an absolute prerequisite to cancer," says Lowndes. "Once you set up just the right amount of genomic instability, within a few decades you can develop the six to seven mutations to create a cancer. If you mutate one of the very guardians of genomic stability then you set up genomic instability."
Studying the pathway in detail represents a considerable challenge however. Its key initiating proteins are not abundant, so getting enough protein for biochemical analysis is difficult, says Lowndes.
Understanding exactly how it works could lead, however, to important new drugs that could boost or block elements of the pathway as a way to prevent or treat cancers.