Institut de Biologie StructuraleGrenoble / France

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Recognition of DNA Lesions

Recognition of DNA lesions

The ability of cancer cells to repair DNA damage after chemo- or radiotherapy significantly reduces the efficiency of available treatment. As a result, proteins involved in DNA repair pathways are now being viewed as potential drug targets. At present, screening and designing specific inhibitors for these new drug targets are largely dependent on the availability of high-resolution crystal structures of these essential DNA repair enzymes and a more detailed understanding of the molecular mechanisms underlying these processes.

Nucleotide Excision Repair (NER) and Base Excision Repair (BER)

NER is responsible for the repair of very diverse DNA lesions, such as bulky adducts or UV-induced lesions, and involves the recognition and subsequent removal of damaged DNA by a dual-incision event. In prokaryotes, this process is carried out by the four Uvr proteins and recent studies reveal that efficient recognition of such a broad set of lesions is largely accomplished by a single protein, UvrA. In contrast the BER enzymes, responsible for repairing base lesions associated with oxidative stress, are very different in that each enzyme recognises a very small set of chemically related DNA lesions and hydrolyses the N-glycosidic bond of the aberrant base.

Research Goals

Our goal is to study the substrate specificity and determine the high-resolution crystal structures of D. radiodurans UvrA and two human BER enzymes, associated with increased risks of cancer, in complex with oligonucleotides containing DNA lesions. Our long term goal is to analyse these crystal structures in view of known mutations in these genes associated with cancer predispositions and to use them to design specific inhibitors that could be used to potentiate the efficacy of drugs currently used in chemo- or radio-therapy.

A . Structures of DNA lesions induced by UV radiation. CPD: cyclobutane pyrimidine dimer. B. Crystal structure of D. radiodurans UvrA2. C. Common base modifications associated with oxidative stress.