Current issue
The rise of telomeres
Rockefeller scientist proposes a theory
of how telomeres evolved from tiny
loops at the ends of chromosomes
BY RENEE TWOMBLY
“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
|
|
Archive Search
|
|
Editor
Zach Veilleux
Science Writers
Lauren Gravitz
Kristine Kelly
Assistant Editor
Talley Henning Brown
Art Direction
Bolle Design, NYC
Copyright © 2006
The Rockefeller University
|
