Sci. Aging Knowl. Environ., 5 May 2004
DNA-break repair pathway poops out in older cells
Like students whose motivation level wanes as summer nears, a molecular crew that mends fractured DNA gets lazy toward the end of an animal's life, according to new work. The findings spotlight a pathway whose breakdown could explain how elderly genomes become riddled with errors, which boosts cancer risk.
Older cells rack up large DNA deletions and rearrangements. Such scars often appear because cells fail to fix a type of damage in which both DNA strands break. Cells copy missing information from an unscathed sister strand into the frayed region, a process called homologous recombination, or they use one of several methods of nonhomologous end joining to fuse the ragged ends. Mice and humans with defects in these repair mechanisms display symptoms of premature aging (see Cheng and Bohr Perspective). These observations suggest that the ability to patch double-strand breaks helps keep creatures young. Furthermore, normal animals accumulate these breaks as they grow older, raising scientists' suspicions that the ability to combat such insults diminishes with age. Although researchers had previously shown that other types of DNA repair falter with age, no one had established an age-dependent decline in pathways that target double-strand breaks.
To address the question, Vera Gorbunova, a molecular gerontologist at Baylor College of Medicine in Houston, Texas, and colleagues experimented on cultured human connective tissue cells called fibroblasts. The researchers tracked nonhomologous end joining in young, middle-aged, and old fibroblasts by infusing the cells with a tattered DNA snippet that encodes a green fluorescent protein. Because cells make this protein only after mending the template's broken ends, the proportion of green cells reflects fix-it capability. End-joining efficiency declined in middle-aged cells compared with young cells, and it dropped even further--nearly fivefold--in old cells. Sequencing the repair junctions of the green cells' DNA revealed that young cells mended DNA precisely, whereas the others frequently harbored gaps at these sites. Among cells with such deletions, the old group didn't appear to apply a certain nonhomologous end-joining mechanism that the young and middle-aged cells often used. Taken together, the findings could help explain how elderly genomes get fouled up. "Double-strand break repair becomes less efficient and sloppier," Gorbunova says.
According to biologist Philip Hanawalt of Stanford University, the work "clearly documents a striking difference" in the ability of young and old fibroblasts to refurbish double-strand breaks. He and Gorbunova caution that laboratory-grown cells might not mimic the behavior of their counterparts inside an animal. If the work pans out, however, it might help explain why the incidence of cancer increases exponentially with age, says Thomas Kunkel, a molecular geneticist at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina (see "Dangerous Liaisons"). Tumor cell DNA teems with errors, and the work supports the notion that deteriorating double-strand break repair contributes to this phenomenon, Kunkel says. It also encourages further research into why the DNA-break repair crew fails to make the grade at the end of our lives.
May 5, 2004
Suggested by Nick Bishop.
Science of Aging Knowledge Environment. ISSN 1539-6150