Potential Mechanisms to Maintain Genome Integrity Identified
The fundamental causes of certain “mistakes” in our DNA that can lead to the development of cancer and many other human diseases have remained unknown. As reported in the August 20, 2009 issue of the journal Nature, Dr. Richard Kolodner and his colleagues at LICR’s San Diego Branch made a discovery that may have solved this mystery. The team identified a large number of genes and their related pathways that act to prevent large-scale changes in chromosome structure known as Gross Chromosomal Rearrangements (GRCs). If linked to cancer progression, these genes could be important therapeutic targets.
GRCs often occur in specific regions of the human genome that are prone to instability, such as stretches of DNA that contain repetitive sequences. Because these “at-risk” regions occur somewhat frequently within the relatively stable human genome, the team reasoned that specific mechanisms must be present to prevent genome rearrangements. This is exactly what they found.
Using an assay system based on yeast, Dr. Kolodner and his team compared the accumulation rates and properties of GRCs in chromosomal regions containing single-copy sequence to regions with repeated sequence. They discovered that different pathways contribute to the formation and suppression of GRCs in the “at-risk” regions than in single-copy sequence. These pathways, known to be involved in maintenance of the genome, include mismatch repair genes, replication checkpoint genes and genes involved in chromatin remodeling.
Kolodner’s team demonstrated, for the first time, how large-scale genome instability is prevented in “at-risk” repetitive DNA sequences. If the genes identified by the team are mutated in cancer, Kolodner plans to target them. They will have their work cut out for them, however, as their list is predicted to include 500-1000 human genes.