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A new ending to an old "tail"

tumor cells

About 10 percent of tumor cells use a mechanism called ALT, short for alternative lengthening of telomeres, to keep their chromosomes ends intact. PML bodies that contain telomeric DNA and associated telomere-binding proteins (shown in orange) are highly characteristic of ALT tumor cells.
Image: Liana Oganesian, Salk Institute for Biological Studies.

In stark contrast to normal cells, which only divide a finite number of times before they enter into a permanent state of growth arrest or simply die, cancer cells never cease to proliferate. Scientists in the lab of Jan Karlseder have uncovered an important clue to one of the mechanisms underlying cancer cell immortality. Their findings reveal an unanticipated structure at chromosome ends, which could be a key ingredient in the biological "elixir of life."

"How tumor cells evade cell death is still baffling to us, but we think we may have solved a small piece of this puzzle," says Karlseder.

A linchpin to the immortality of malignant cells is the ability to maintain telomeres, the specialized ends of chromosomes. Like slow-burning fuses, telomeres become shorter each time a cell divides, acting as a kind of cellular clock ticking down a cell's age. Eventually they are depleted, and the cell enters a permanently arrested state called senescence. To escape this inevitable demise, about 90 percent of human tumors rely on a huge boost in the levels of an enzyme called telomerase, which adds DNA to telomeres, thus turning the clock back. The remaining 10 percent use a mechanism known as ALT, short for alternative lengthening of telomeres. Understanding ALT is essential since tumors can evade anti-cancer therapies aimed at inhibiting the activity of telomerase through the activation of ALT.

Trying to learn more about the biological tools that ALT tumors use to sustain their immortal status, Karlseder and his team uncovered a new structural beacon, called the C-tail—a string of DNA rich in the base cytosine (C) that hangs over the very tip of telomeres. The finding came as a big surprise since conventional wisdom had it that mammalian cells normally terminate both ends of every chromosome with a single-stranded stretch of DNA rich in the base guanine (G).

When postdoctoral researcher Liana Oganesian carefully looked at chromosome ends, however, she discovered that about half of all telomeres in AL T tumors bore a C-tail, while the presence of such a tail in normal human cells was several hundredfold less prevalent.

"This piece of DNA is conspicuously absent in tumors that use telomerase, suggesting that C-tails are a unique feature of ALT tumors," she says, and potentially opening up new therapeutic avenues to cut the life of a cancer cell short.