Exonucleases Attack Chromosomes with Shortened Telomeres

Researchers have found that enzymatic attack at the ends of shortened telomeres is the principal early cause of loss of genetic information and occurs before repair enzymes fuse shortened telomeres together. They postulated that enzymatic damage occurs before telomeres fuse and become randomly broken during subsequent cell divisions.

Telomeres are a complex of repetitive DNA sequences that cap the ends of chromosomes. Telomeres play a role in cellular replication via the telomerase enzyme, which helps determine whether cells are able to replicate. Telomeres shorten each time a cell divides, and signal cell senescence when they reach a critical length.

Investigators at Johns Hopkins University (Baltimore, MD, USA) worked with a yeast model to establish the sequence of events that occur when telomeres become shortened. They inserted genetic markers into a yeast chromosome and followed the loss of these markers as the telomeres shortened. Their paper in the December 2003 issue of Molecular and Cellular Biology revealed that markers at the very end of the chromosome were most likely to be lost, and markers closest to the center of the chromosome the least likely.

"If fusion and breakage was the primary mechanism of gene loss, the pattern of loss would have been random--each marker would have been just as likely as the others to be lost,” explained senior author Dr. Carol Greider, professor of molecular biology and genetics at the Johns Hopkins School of Medicine. "The marker loss we saw was not at all random, so we knew some other mechanism was at work. We demonstrated that fused chromosomes do break randomly, at which point exonucleases attack the exposed ends. Fusion is a big part of what leads to major genomic instability when telomeres aren't working, but it's not the initial problem. Our discovery should spark researchers in the field to think along new lines.”




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