Sci. Aging Knowl. Environ., 26 May 2004
Multiple paths lead to senescence
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/21/nf54
Cells, like people, lose their vitality, and researchers are eager to track down the mechanisms that prompt normal cell life to screech to a halt. New research helps enumerate the proteins that make cells stagnate when chromosome ends fray--and reveals that one protein halts cells by other means. The findings bolster the idea that signals other than eroding telomeres can shut down cells.
Cultured cells eventually stop dividing and enter a state known as senescence. This phenomenon might spur aging by draining stem cell pools (see "Backup Plan," "Faustian Bargain," and Campisi Perspective). Researchers have uncovered a pathway to senescence that begins with short telomeres, the protective caps that guard the ends of chromosomes. Stumpy telomeres activate a protein relay: p53 switches on p21, which fires up RB, which halts cell division. Another protein, p16, also contributes: It activates RB, and amounts of the molecule escalate in senescent cells. But whether p16 responds to short telomeres has sparked controversy. Some results suggest that the protein accumulates when telomeres fizzle, but others suggest that p16 and p21 amass in different cells (see "Random Acts" and Sharpless Perspective).
To investigate the p16-telomere connection, molecular biologist John Sedivy of Brown University in Providence, Rhode Island, and colleagues nurtured human connective tissue cells in culture. They added dyes that color telomeres and then looked for DNA-damage proteins, which mark tattered ends. In keeping with previous work, few cells that had divided only several times accumulated damage-repairing proteins at telomeres, but 70% of cells near senescence harbored such molecules at these sites. Also matching previous findings, quantities of p21 and p16 rose as cells aged. However, p21 tended to collect in cells in which damage-response proteins had flocked to telomeres, whereas p16 did not. The results suggest that p21, but not p16, responds to marred telomeres.
To further investigate the machinery that reacts to short telomeres, the researchers cataloged the DNA-damage proteins that assemble on chromosome ends. They found that the protein called ATM--which detects breaks in double-stranded DNA--migrates to telomeres in old cells. Its relative ATR--which gloms onto inappropriately single-stranded regions--does not. However, when the researchers blocked ATM, ATR bound telomeres. The results suggest that cells recognize eroding telomeres as breaks in DNA rather than as single-stranded regions, says Sedivy, and that ATM normally responds to those molecular wounds, although ATR can step in if necessary.
The results bolster the idea that p16 works through a signal other than shortened telomeres, says molecular oncologist Norman (Ned) Sharpless of the University of North Carolina in Chapel Hill. Sedivy says he's probing why p16 quantities rise in senescent cells by tracking proteins known to activate the p16 gene. Cancer researcher Denise Galloway of the Fred Hutchinson Cancer Research Center in Seattle, Washington, notes that the work makes a new distinction between the roles of ATM and ATR at telomeres in senescent cells, providing new mechanistic details about how short telomeres halt cell division. Further work should reveal how cellular senescence--triggered by short telomeres and other signals--fosters aging in animals.
May 26, 2004
Suggested by Greg Liszt.
Science of Aging Knowledge Environment. ISSN 1539-6150