Friday June 26 2009
CEA
These findings suggest that OGG1-Cys326, which is more amenable to oxidation under oxidative stress, has a lower ability to repair the DNA damage caused by this same oxidative stress, and that molecules possessing this protein would subsequently be far more conducive to the accumulation of mutations. This breakthrough discovery could explain epidemiological findings that suggest an association between presence of the variant and an increased risk for certain cancers, particularly lung/prostate cancer and gastric cancer.
A section of the population proves more vulnerable to oxidative stress
CEA
There is group of proteins that is tasked with repairing DNA damage, especially that caused by oxidative stress. A team from the Laboratory of Genetic Instability Research (iRCM, Fontenay-aux-Roses) has demonstrated that one of these proteins has a variant that possesses a weaker reparative activity, and consequently allows a build-up of DNA mutations. The team identified the mechanisms that shape this activity.
The DNA in every body cell is constantly under attack, and the damage done is detected and repaired by various proteins. The reactive oxygen species (ROS) produced as we breathe is one of the actors instigating this damage. ROS concentrations are increased in the oxidative stress situations encountered in numerous diseases (including inflammatory disease, cancer, and neurodegenerative disease) as well as during exposure to radiation or to many different compounds. The most common ROS-caused DNA lesion is 8-oxoG (oxidation of guanine, one of the DNA nucleobases, into 7,8-dihydro-8-oxoguanine). This DNA lesion is identified and then removed by a protein called OGG1 (for 8-oxoguanine DNA glycosylase), which is normally resident in our cells. However, if this protein is deficient or completely missing, the coast is clear for mutations to accumulate, which can lead to the development of cancers.
The human population carries essentially two forms of OGG1, called variants. Our proteins are built of a combination of amino acids that can sometimes differ between individuals, in what is known as a gene polymorphism. The most frequently-occurring form of OGG1 protein has a serine in position 326 (OGG1-Ser326). The other form has a cysteine molecule instead of the serine (OGG1-Cys326). This variant is found in 20%–30% of individuals in European Caucasian populations and 40%–60% of individuals in East-Asian populations.
The Laboratory of genetic instability research (LRIG) has focused research on these proteins. LRIG teams have demonstrated that cells possessing the OGG1-Cys326 morphotype show greater genetic instability and two-fold lower 8-oxoG lesion repair than cells that possess the more common morphotype. They also showed that this drop in activity was due to oxidation of the cysteine-326 residue. Cysteine is in fact far more vulnerable to oxidation than serine.
These findings prompted the LRIG team to cross-compare the two OGG1 variants in terms of vulnerability to oxidative stress. They found that this type of oxidative stress had a stronger inhibitive effect on OGG1-Cys326 repair mechanisms.
The human population carries essentially two forms of OGG1, called variants. Our proteins are built of a combination of amino acids that can sometimes differ between individuals, in what is known as a gene polymorphism. The most frequently-occurring form of OGG1 protein has a serine in position 326 (OGG1-Ser326). The other form has a cysteine molecule instead of the serine (OGG1-Cys326). This variant is found in 20%–30% of individuals in European Caucasian populations and 40%–60% of individuals in East-Asian populations.
The Laboratory of genetic instability research (LRIG) has focused research on these proteins. LRIG teams have demonstrated that cells possessing the OGG1-Cys326 morphotype show greater genetic instability and two-fold lower 8-oxoG lesion repair than cells that possess the more common morphotype. They also showed that this drop in activity was due to oxidation of the cysteine-326 residue. Cysteine is in fact far more vulnerable to oxidation than serine.
These findings prompted the LRIG team to cross-compare the two OGG1 variants in terms of vulnerability to oxidative stress. They found that this type of oxidative stress had a stronger inhibitive effect on OGG1-Cys326 repair mechanisms.
These findings suggest that OGG1-Cys326, which is more amenable to oxidation under oxidative stress, has a lower ability to repair the DNA damage caused by this same oxidative stress, and that molecules possessing this protein would subsequently be far more conducive to the accumulation of mutations. This breakthrough discovery could explain epidemiological findings that suggest an association between presence of the variant and an increased risk for certain cancers, particularly lung/prostate cancer and gastric cancer.
Only low quantities of ROS are produced under normal cell metabolism, but disease or exposure to radiation or numerous chemical compounds triggers massive ROS production. These species create oxidative DNA lesions, the most abundantly-found being 8-oxoG. They are equally capable of inactivating the OGG1 protein responsible for repairing these lesions. This inactivation hits the OGG1-Cys326 form harder than the OGG1-Ser326 form, as it is more oxidation-vulnerable. The net result is that cells carrying the OGGI-Cys326 morphotype promote mutation accumulation.