Hanging Out
Authors: Beckman Mary 
Published: August 2003

Like a construction worker whipping a flag in the air to slow down drivers, chromosomes might wave molecular pennants to stop cells from growing. A new study provides the first evidence that dangling sequences at chromosome tips could signal cells to put the brakes on division.

Some cultured cells divide a limited number of times, pausing in a state called senescence that might contribute to aging (see
"More Than a Sum of Our Cells"
). Abnormal or very short chromosome ends somehow prod cells toward the senescent state, but the details remain obscure. Due to a quirk in the DNA replication machinery, the very ends of chromosomes can't be copied. As a result, telomeres--structures at the ends of chromosomes composed of repeated DNA sequences and proteins--shorten each time the cell duplicates. Telomeric DNA is mostly double-stranded, just like the rest of the chromosome. At the tip, however, one strand is longer than the other and juts out as a single-stranded piece of the repeated sequence. Rather than flop around in the wind, this overhang tucks itself neatly into the chromosome stub in healthy cells. A protein called TRF2 apparently pins it there and helps strengthen telomeres. Altered forms of TRF2 cause the tidy end to unravel.

Short or disrupted, unpacked telomeres induce senescence or cell death through a biochemical pathway that responds to DNA damage, but no one understands exactly how. Dermatologist Barbara Gilchrest and colleagues at Boston University School of Medicine wondered whether an exposed overhang alerts the emergency system and sends skin cells down the senescent path. She reported the results 18 September 2002 at The Science and Technology of Skin Aging, 2nd International Symposium in Cleveland, Ohio.
To test whether the loose end might spur senescence, the researchers constructed three short pieces of DNA. One was a copy of the dangling sequence, a single-stranded bit of the telomere repeat. The two controls were the mirror image of the repeat sequence and a random sequence. The researchers dribbled these snippets onto cells in culture and looked for signs of senescence. Only the overhanglike sequence caused the cells to spread out as if ready to snooze and to make an enzyme that characterizes senescent cells. To determine whether the overhang imitator simulated telomere unfurling, the researchers identified the proteins that cells made in response to the DNA scrap and when they were engineered to produce a disruptive form of TRF2. Both treatments incited the cells to produce the same DNA damage response proteins, including a head honcho called p53 that normally prevents cells from turning cancerous. Gilchrest suggests that short telomeres acquired after many divisions might unravel and wave the overhang as an SOS flag.
The research provides evidence for "the idea that the single-stranded overhang could be the [senescence] signal," says molecular biologist Calvin Harley of Geron Corp. in Menlo Park, California, although more experiments are needed to nail down the hypothesis. Knowing what the construction worker's flag looks like will help researchers navigate this stretch of road.
--Mary Beckman

B. Gilchrest, Evidence that exposure of the 3' telomere overhang signals for aging. The Science and Technology of Skin Aging, 2nd International Symposium, 18 to 20 September 2002, Cleveland, Ohio.
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