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DNA repair mechanisms ensure
that the genetic information contained in the nucleus of the cells of
living organisms will remain intact from one generation to the next. One
repair mechanism in particular eliminates a certain number of lesions
of DNA damaged by endogenous and exogenous agents. Alexander Ishchenko
and Murat Saparbaev, researchers working on a CNRS team(1)
, have just elucidated a new pathway, which makes it possible to identify
new genes that predispose humans to cancer. From a pharmacological point
of view, this discovery, published in the January 10, 2002 issue of Nature,
opens horizons for new targets for specific cancer chemotherapies.
Life in the presence of oxygen leads to the production of highly reactive
derivatives of this molecule, known as reactive oxygen species (ROS)(2)
. More than one hundred lesions on the DNA(3) , which
holds the hereditary material of living organisms, induced by these ROS
are known to researchers. During DNA replication, these lesions, including
the modified bases, can have two particularly damaging effects. They can
either block DNA replication and lead to cell death, or cause modification
of the genetic information. In the second case, this gives rise to a mutation
that may induce the cancerous process.
To combat the damaging effects of these lesions, living organisms are
equipped with various mechanisms to repair DNA, thus ensuring the stability
of the genome. Certain mechanisms eliminate the bases that have undergone
structural alterations. In humans, some mechanisms may be defective and
cause diseases such as Xeroderma Pigmentosum(4) , Ataxia
Telangiectasia(5) and Cockayne's Syndrome(6).
Defects present in other repair pathways are also implicated in the appearance
of cancers of the breast and colon. It is therefore necessary to understand
the various repair pathways that ensure that living organisms function
correctly.
Research has brought to light DNA bases modified by small- or large-sized
molecules, and repaired by specific repair mechanisms. Generally speaking,
the bases modified by the ROS and the small-sized molecules are eliminated
by the repair pathway known as "base excision." This particular
repair mechanism also contributes to the stability of the genome. It involves
the sequential action of various proteins, the first being a DNA glycosylase,
an enzyme that specifically excises the modified base. J. Laval, working
in Villejuif (France), established the first stages of the molecular mechanism
of this repair pathway. However, this pathway did not explain certain
genetic observations or the resistance of certain tumoral cells to the
action of cytotoxic agents.
The new pathway described by Alexandre Ishchenko and Murat Saparbaev both
repairs the DNA bases modified by small- or large-sized molecules and
replaces them. This metabolic pathway is found in bacteria, yeast and
humans. In the first stage, it requires a specific endonuclease, an enzyme
that excises the strand of DNA next to the damaged base. In the subsequent
stages, the modified base is eliminated and replaced by the original base
through the sequential action of other enzymes. This repair pathway is
an alternative to base excision repair. It has the advantage of not inducing
mutagenic and/or cytotoxic molecular intermediates, and of being potentially
more efficient for the cell.
This discovery explains a certain number of genetic observations in Escherichia
coli and mice from a biological point of view. It makes it possible to
identify new genes that predispose humans to cancers, and opens horizons
for new therapeutic targets.
Reference:
"Alternative nucleotide incision repair pathway for oxydative DNA
damage" by Murat Saparbaev and Alexander Ischenko, Nature,
January 10, 2002.
(1) UMR 8532 CNRS- Laboratoire "Physicochimie et
pharmacologie des macromolécules biologiques" (Physicochemistry
and Pharmacology of Biological Macromolecules Laboratory), Director: C.
Auclair, Institut Gustave Roussy, Villejuif, and LBPA-ENS, Cachan.
(2) ROS are generated by the cellular metabolism, certain
drugs and ionizing radiation. If they are not eliminated, they react with
the cellular constituents: DNA, proteins and lipids.
(3) DNA constitutes the genetic material of life. It is
a double helix that contains the genetic code based on the reading of
the sequence of the Adenine, Guanine, Thymine and Cytosine bases. An Adenine
or Guanine base on a strand has a corresponding Thymine or Cytosine on
the opposite strand. These are known as the complementary base pairs.
If a base is damaged by ROS, the Adenine : Thymine or Guanine : Cytosine
complementarity is modified and said to be erroneous.
(4) Patients suffering from Xeroderma Pigmentosum disease
are highly sensitive to sunlight, and develop skin cancers at a very early
age.
(5) Patients suffering from Ataxia Telangiectasia are
hypersensitive to ionizing radiation.
(6) Patients with Cockayne's Syndrome develop, among other
disorders, neurodegenerative disorders.
CNRS researcher
contacts:
Dr. Saparbaev Murat
UMR 8532 CNRS
Institut Gustave-Roussy
Tel: + 33 1 42 11 54 04
E-mail: smurat@igr.fr
Dr. Jacques Laval
UMR 8532 CNRS
Institut Gustave Roussy
Tel: + 33 1 42 11 48 24
E-mail: jlaval@igr.fr
CNRS Life Sciences Department contact:
Marie-Pascale Corneloup-Brossollet
Tel: + 33 1 44 96 46 48
E-mail: marie.corneloup@cnrs-dir.fr
Press contact :
Stéphanie Bia
Tel: + 33 1 44 96 43 09
E-mail: stephanie.bia@cnrs-dir.fr
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