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The rise of telomeres
Rockefeller scientist proposes a theory of how telomeres evolved from tiny loops at the ends of chromosomes
“As scientists get older, they often start thinking about evolution or decide they have to figure out the brain,” says Titia de Lange, head of Rockefeller’s Laboratory of Cell Biology and Genetics.
de Lange is starting to think about evolution.
Her recent opinion piece, published by Nature Reviews, constructs a framework for the evolution of one of the cell’s most mysterious and complex systems, telomeres, which de Lange has spent her career studying.
Telomeres are specialized protein–DNA complexes that cap the ends of chromosomes. Like the plastic sleeves that stop shoelaces from unraveling, they protect the sequences that are needed for DNA to replicate when cells divide. Telomeres are enormously complicated machines made up of specialized DNA, an enzyme called telomerase, and protein complexes that interact with DNA. They function to regulate the lifespan of a cell by shortening with each cell division until they become too small to serve their function and cause the cell to cease dividing.
“But things started out very simply,” de Lange says. She suggests that tiny structures called telomeric-loops (“t-loops”), which she and her collaborators discovered four years ago, are actually remnants of the original telomere system that served to protect the ends of the first linear chromosomes found in early microorganisms. The investigators have shown that without these little loops, cells mistake the exposed chromosome ends for sites of DNA damage and when they attempt to repair them, the cells die.
When eukaryotic cells — those with distinct nuclei — first developed about 1.8 billion years ago, their chromosomes evolved to become linear in shape, rather than circular, as they were in prokaryotic cells, which lack nuclei. Many biologists have theorized that telomerase was born at the same time in order to protect the newly exposed ends of linear chromosomes.
But de Lange says t-loops may have existed even before telomerase evolved. “The eukaryotic t-loop looks a lot like a structure that could have been formed in prokaryotes before eukaryotes evolved,” she says.
If the chromosomes of a microorganism, such as the bacterium that gave rise to eukaryotes, were linear, a t-loop could easily be formed from just a few repeats at the end of the chromosome, de Lange says. All the enzymes to make t-loops were already available; they were used for regular DNA replication in bacteria. “When E. coli is replicating its DNA, occasionally the newly synthesized fork collapses, leaving the end of the new DNA hanging out of a half-replicated E. coli genome.”
E. coli has a mechanism to deal with this. Enzymes take the extruded DNA and reinsert it back into the genome. This reaction is similar to the formation of a t-loop. “Through regular DNA synthesis, you have the chance to extend the end of the inserted DNA in the t-loop, just as the telomerase enzyme does,” de Lange says. “All you need to get this primitive telomere system to work are a few repeats at the end of the linear DNA.”
As proof of this notion, de Lange points to several proteins that currently act at telomeres that have evolved from the enzymes in E. coli that are involved in replication restart events. There are also prokaryotic relics of this system — de Lange calls them living fossils — in which linear chromosomes have repeats of varying sequences and sizes at their ends. These living fossils survive with linear chromosomes because they have miniature t-loops, de Lange says.
“What I’m suggesting is that the first eukaryotes had t-loops made by these replication enzymes, and that’s all they needed,” says de Lange, the university’s Leon Hess Professor. “Later, telomerase arose from evolutionary pressure to select cells that came up with the more elegant solution we have today.”
Not only can telomerase make new telomeres where none are present, but it can ensure that all chromosome ends have the same sequence. “In this early t-loop evolution model, every end could have had a different sequence, a form of telomere anarchy. When you have the same sequence at all ends — in most eukaryotes it’s TTAGGG — you can evolve proteins that specifically bind to that sequence,” says de Lange.
“Now you can start regulating the whole thing, and begin fussing over events, building a bureaucratic committee of proteins that bind to the TTAGGG sequence and help regulate how telomeres behave. This is what eukaryotes like to do: control things through the use of large committees.”

May 14, 2004



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