Normal Chromosome Ends Elicit A Limited DNA Damage Response

The natural ends of chromosomes look just like broken strands of DNA that a cell's repair machinery is designed to fix. But mending chromosome ends, or telomeres, would set the stage for the development of cancer in successive generation of cells.

To prevent the cell's DNA repair machinery from confusing telomeres with broken strands of DNA that need to be repaired, the tips of chromosomes are tucked in and shielded by a phalanx of proteins, forming a protective "cap".

Ironically, to form this protective structure at the end of chromosomes, nature solicited help from the very same repair machinery whose misguided repair attempts the cap is supposed to hold at bay, reports the Salk team, led by Jan Karlseder, in the current issue of Molecular Cell.

Scientists had long surmised that the protective telomere-protein complex had to unravel when enzymes need to gain access in order to copy the chromosome's DNA in preparation for cell division. And if so, they wondered, why didn't the presumably exposed chromosome ends trigger a DNA damage response?

Turns out they do, at least to a limited extend.

"During a small window right after DNA replication, when the cell gets ready for cell division, chromosome ends are exposed," says research fellow and first author Ramiro Verdun who emphasizes that, "it would be very unhealthy for the cell if it happened at any other time."

In addition, Verdun and his colleagues found that several well-known members of the DNA damage response machinery -- recruited by the now unprotected telomeres -- congregate at the tips of chromosomes.

"We believe that the localization of repair proteins to chromosome ends, and detection of telomeres as damage at this precise time are necessary to trigger the re-formation of a protective telomeric structure," says Karlseder, an assistant professor in the Regulatory Biology Laboratory.

In contrast to damaged strands of DNA, they hypothesize, the repair process never gets fully underway at telomeres. Instead, the very tips of the chromosomes are looped back, tucked in and covered with telomeric proteins.

"The cell tries to fix everything to make sure that the genetic information is safe and complete for the next generation of cells," says Verdun. "But in the case of healthy chromosome tips or telomeres, repair would have disastrous consequences," he adds.

Repairing telomeres would randomly fuse whole chromosomes end-to-end. During the next cell division the sorting mechanism, which ensures that each daughter cell receives a full complement of chromosomes would inevitably rip the fused chromosomes apart.

"Such fusion breakage cycles scramble the genome over time, and cause genome instability, which is a hallmark of cancer cells," explains Karlseder. "This demonstrates the importance of telomeres in preserving genome integrity and preventing cancer development."

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes. For more information: www.salk.edu.