Winding Up to Wind Down

Abstract

Remodeling doesn't always renew. According to work published last week, old cells lose a protein that keeps DNA slack and active and, consequently, the cells restructure their chromatin. As a result, a gene that spurs cell division tightens up and the cells stall in the dormant state known as senescence. The study is the first to pinpoint a senescence-related molecular change that reshapes chromatin. Cells growing in culture eventually stop dividing, apparently because telomeres, the caps on the ends of their chromosomes, unravel. Whether senescence is more than a cell-culture phenomenon remains controversial, but it might keep cancer cells from running rampant; late in life, senescence might also hasten aging by tranquilizing reserves of irreplaceable cells or destroying tissue (see "Tissue-Tampering Turn-On," "More Than a Sum of Our Cells," "Dangerous Liaisons," and Campisi Perspective ). When cells senesce, their repertoire of active genes shifts dramatically. How tightly DNA coils around proteins called histones influences gene activity, so Bandyopadhyay and colleagues wondered whether proteins that modulate the packing might contribute to senescence. To address the issue, the team grew skin pigment cells in culture and tracked p300, a histone acetyltransferase (HAT) protein. HATs add acetyl groups to histones, which loosens their association with DNA. When the cells senesced, concentrations of p300 dropped dramatically. The researchers also tested cells that avoid senescence because they're engineered to produce the telomere-maintaining enzyme telomerase; their p300 concentrations remained elevated. In addition, a chemical inhibitor of p300 or a crippled form of the protein spurred senescence. The results suggest that loss of p300's HAT activity encourages senescence. The team then assessed whether a drop in p300 quantities might lead to changes in the activity of a gene thought to regulate senescence. The gene's protein product, cyclin E, nudges cells to divide; artificially cranking it up can override some senescence signals. When p300 amounts tailed off in old cells, cyclin E concentrations also plummeted, the researchers found. In addition, the histones that spool the cyclin E gene carried fewer acetyl groups in old cells than in young ones. These observations suggest that a loss of p300 reduces the acetylation--and as a result, the activity--of the cyclin E gene, thereby blocking cell division and fostering senescence. "The idea that changes in chromatin [structure] occur in senescent cells has been around for a long time, but nobody has been able to get their hands on the proteins that make these changes," says molecular biologist Judith Campisi of Lawrence Berkeley National Laboratory in California. The new study "nails down" one of those proteins, she says: "They've done a really good job of showing that p300 plays an essential role in senescence of [pigment cells]." Most work on senescence has focused on connective tissue cells called fibroblasts, Campisi adds; studies such as this one that examine other cell types will expose common paths that different cells take toward their demise and might suggest ways to refurbish aging bodies. --R. John Davenport; suggested by Patrick Kaminker D. Bandyopadhyay, N. A. Okan, E. Bales, L. Nascimento, P. A. Cole, E. E. Medrano, Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes. Cancer Res. 62 , 6231-6239 (2002). [Abstract] [Full Text]