Oxidatively Damaged DNA Repair Defect in Cockayne Syndrome and its Complementation by Heterologous Repair Proteins

Guido      Frosina

doi:10.2174/092986708784049586

Abstract

Cockayne syndrome (complementation groups A and B) is a rare autosomal recessive DNA repair disorder characterized by photosensitive skin and severely impaired physical and intellectual development. The Cockayne syndrome A and B proteins intervene in the repair of DNA modifications that block the RNA polymerase in transcribed DNA sequences (transcription-coupled repair). Recent results suggest that they also have a more general role in the repair of oxidative DNA base modifications. Although the phenotypical consequences of defective repair of oxidatively damaged DNA in Cockayne syndrome are not determined, accumulation of oxidized lesions might contribute to delay the physical and intellectual development of these patients. To conceive new therapeutic strategies for this syndrome, we are investigating whether the oxidatively damaged DNA repair defect in Cockayne syndrome might be complemented by heterologous repair proteins, such as the Escherichia coli formamidopyrimidine-DNA glycosylase and endonuclease III. The complementation studies may shed light on the important lesions for the Cockayne syndrome phenotype and offer new tools for future therapies aimed at counteracting the consequences of oxidatively damaged DNA accumulation.

Keywords: Cockayne syndrome, DNA base excision repair, 8-oxo-7,8-dihydroguanine, neurological deterioration, aging, transcriptioncoupled repair, formamidopyrimidine DNA glycosylase, endonuclease III