Kansas City, Mo. (Aug. 21, 2008) - The Stowers Institute’s Baumann Lab has discovered that a little-studied pathway plays a critical role in chromosome fusion — a misguided attempt by chromosomes to repair damage to their ends, which can put cells on the path to becoming cancerous. The work appears in today’s issue of Molecular Cell.

     Occasionally, cells mistake the ends of their chromosomes for a break and activate the cellular machineries for double-strand break repair causing the chromosome end to fuse. Fusions occur either with the other end of the same chromosome (forming a relatively stable circular chromosome) or with another chromosome (forming a volatile dimer of chromosomes).

     Gross chromosomal rearrangements allow for an accumulation of mutations that can eventually convert a cell from a pre-cancerous state to a cancerous one, so chromosome fusion — especially inter-chromosome fusion — can lead to cancer.

     Inter-chromosome fusions are delicate and are likely to re-break and re-fuse in new combinations of ends many times over, making them difficult to study. The Baumann Lab conducted its work using fission yeast, a model that is likely to fuse into more cooperative circular chromosomes. The same mechanism is believed to be responsible for both types of fusion.

     “Despite the significance of telomere dysfunction in genome instability and cancer development, very little is known about the repair factors that mediate chromosome end fusions,” said Xiaorong Wang, Ph.D., Postdoctoral Research Associate and first author on the paper. “We found that fusions are mediated by a rarely studied pathway called single-strand annealing (SSA). This was a great surprise, as previous work had almost ruled out recombinational repair pathways from mediating chromosome fusions.”

     “Combining genetic and molecular biological approaches, our study characterized the fusion junctions and the specific repair factors responsible for fusions in fission yeast cells when telomeres are lost,” said Peter Baumann, Ph.D., Assistant Investigator and senior author on the paper. “Furthermore, we discovered that different types of chromosome end damage, for example a gradual telomere shortening versus a mutation in a telomere binding protein, activate different pathways to trigger chromosome fusion.”

     These findings provide important and unexpected clues into the mechanisms of chromosome fusions in higher organisms. The discovery of novel functions of SSA factors at telomeres suggests that the pathway may play a far more important role than previously anticipated. Further analysis of this DNA repair pathway is expected to shed new light onto how cells defend themselves against DNA damage as well as how misguided repair can contribute to the onset of cancer. To that end, the Baumann Lab has begun investigating the role of human equivalents to the yeast factors identified in this work.

About the Stowers Institute
     Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing and curing disease. The Institute was founded by Jim and Virginia Stowers, two cancer survivors who have created combined endowments of $2 billion in support of basic research of the highest quality.