Roles of the Cockayne Syndrome Group B Protein in Processing Oxidative

Chapter

ABSTRACT

Ch apter 5 Roles of the Cockayne Syndrome Group B Protein in Processing Oxidative DNA Damage and in Protection against Neurodegeneration Meltem Muftuoglu and Vilhelm A. Bohr* AbstractCockayne syndrome (CS) is a segmental premature aging syndrome w ith diverse clinical symptoms that include hypersensitivity to sunlight, severe m ental and physical growth retardation, progressive neurological and retinal degeneration and skeletal abnormalities. The CS complementation group B (CSB) protein is involved in transcription coupled and global genome D N A repair, as well as in general transcription. Recent evidence suggests an additional role for the CSB protein in base excision repair (BER) o f oxidative D N A lesions. Defective repair o f oxidative D N A damage, from endogenous and exogenous sources in CS cells, may be the basis o f the premature aging phenotype and associated neurodegeneration. Introduction Oxidative DNA DamageReactive oxygen species (ROS) are formed in living cells by norm al cellular metabolism and by exogenous sources such as ionizing radiation (IR), hydrogen peroxide (H 20 2) and genotoxic agents. These agents cause oxidative damage to D N A , resulting in the formation o f base and sugar damage, strand breaks and DNA-protein crosslinks.1 D N A base modifications are most prevalent and currendy more than 20 different oxidatively modified bases have been identified.1,2 Among them, 8-hydroxyguanine (8-oxoG) is common and mutagenic. The modified bases can mispair w ith adenine during D N A replication causing G C —*TA transversion.3 8-oxoG is frequently used as a marker o f oxidative levels in organisms. A lthough to a lesser extent than 8-oxoG, 8-hydroxy-adenine (8-oxoA) also possesses premutagenic properties inducing A —*G and A —*C mutations in mammalian cells.4'6 Oxidatively induced D N A damage is mainly repaired by base excision repair (BER), which involves lesion-specific D N A glycosylases in the first step o f the repair process. In the absence o f efficient repair, the accumulation o f oxidatively induced D N A damage leads to mutagenesis and cell death/senescence. These two major oxidative stress induced D N A lesions (i.e., 8-oxoG and 8-oxoA) accumulate in Cockayne syndrome (CS) patients. It has been suggested that a decrease in the repair o f oxidative D N A damage m ight be contributing to the pathogenesis o f CS, notably premature aging (see details below). This is in line w ith the basis o f Harm ans “free