XERODERMA PIGEMENTOSUM AND ATAXIA TELANGIECTASIA:A MOLECULAR CONNECTION BETWEEN NUCLEOTIDE EXCISION REPAIR AND DNA DAMAGE CHECKPOINT

During life cells are subjected to various kinds of damages to their genome, caused by environmental chemical and physical agents, but also by normal cellular metabolism. Surveillance mechanisms, called checkpoints, sense insults to DNA and activate cellular pathways and repair mechanisms, trying to limit the amount of damage and fix the lesions. Nucleotide excision repair (NER) corrects damages causing a distortion of DNA, such as those caused by UV light. Impairment in these control mechanisms have dramatic effects on cells. A paradigm is ataxia telangiectasia (AT), a genetic disease characterized by cerebellar ataxia, immune defects and predisposition to malignancies, which is due to impairments of one of the protein kinases essential for the checkpoint response. Moreover defects in NER are the cause of xeroderma pigementosum (XP) and Cockayne syndrome (CS). XP is a genetic disease characterized by hypersensitivity to sunlight, high incidence of skin cancer and neurological complications. Cockayne syndrome is also a genetic disease and CS patients are photosensitive and display dwarfism and mental retardation. Using yeast, a simple model organism,we identified physical and functional interactions between NER and checkpoint proteins. We found variants of NER factors that are incapable of triggering the checkpoint after UV irradiation. These and other results suggest that repair proteins are responsible for the identification of lesions in the genome and for the function of surveillance mechanisms superintending genomic stability. We plan to define the details of the functional interaction between repair and cell cycle control using genetic approaches and to extend these observations to human cells, by characterizing the molecular defects affecting the DNA damage response in cells derived from XP, CS and AT patients. This work will increase our knowledge of the molecular basis of genetic syndromes such as XP and CS and the possible overlaps with AT.