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For the very first time, researchers have
been able to measure, in real time, what happens when damaged DNA replicates
itself in the cell. This study, led by the team of Robert Fuchs, Director
of the "Cancérogenèse et Mutagenèse Moléculaire
et Structurale" research unit1 , CNRS, Strasbourg, France, shows
how cell machinery replicates its genome despite damage done to DNA. These
results illustrate the mechanism that generates mutations and which is
at the root of all forms of cancer. They are published in the journal
Science dated May 23, 2003.
The genome of all organisms is constantly the
target of numerous chemical and physical attacks that damage the DNA and
therefore endanger the integrity of the genetic message. Many repair mechanisms
are normally responsible for eliminating this damage before replication
incorporates them once and for all into progeny in the form of genetic
mutations. However, it can happen that the replication of genetic material
begins before the DNA has been repaired.
This research gives a picture in real time of what happens when replication
machinery encounters this type of damage. The researchers built a DNA
molecule with damage induced by a chemical carcinogen, introduced this
structure into a cell and analyzed replication intermediates in relation
to time.
Surprisingly enough, we can observe the block of replicative DNA polymerase
(the enzyme that replicates DNA) at the level of the damaged nucleotide.
After a delay of approximately 50 minutes, the replication starts up once
again. Researchers were able to show that the "unblocking" of
the replication fork required the intervention of specialized recently
discovered DNA polymerases. After intervention of these specialized polymerases
in the recopying of the damaged DNA, the replicative machinery steps in
to complete the duplication of genetic material. It should be mentioned
that the cell "pays a high price" for the duplication of its
genetic material by accepting the induction of mutations that result from
the intervention of these specialized polymerases.
The study of these specialized DNA polymerases is a major focus at this
time because they represent potential new pharmacological targets.
Reference:
"Uncoupling of Leading- and Lagging-Strand DNA Replication During
Lesion Bypass in Vivo." Vincent Pages and Robert P. Fuchs, Science
in press, May 23, 2003
1 - The "Cancérogenèse
et Mutagenèse Moléculaire et Structurale" research
unit, CNRS, Strasbourg, has laboratories at the Ecole Supérieure
de Biotechnologie of Strasbourg (ESBS) and the Institut de Recherche sur
les Cancers de l’Appareil Digestif (IRCAD).
"Uncoupling of Leading- and Lagging-Strand DNA Replication During
Lesion Bypass in Vivo." Vincent Pages and Robert P. Fuchs, Science
in press, May 23, 2003
Researcher contacts:
Robert Fuchs
Tel: +33 3 90 24 46 88
E-mail: robert.fuchs@esbs.u-strasbourg.fr
Press Contact CNRS:
Laetitia
Louis
Tel: 01 44 96 49 88
E-mail: laetitia.louis@cnrs-dir.fr
Life Sciences Department contact:
Françoise Tristani
Tel: +33 1 44 96 40 26
E-mail: francoise.tristani@cnrs-dir.fr
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