A prominent hallmark of cancer cells is their inherent genomic instability. Incomplete DNA repair and replication initiate tumours and furthermore accelerate the malignant transformation process. Surprisingly, the machinery responsible for DNA maintenance is also intricately involved in the defence against accelerated aging.
This proposal focuses on two premature aging syndromes tightly linked to cancer and genomic instability. The Werner syndrome protein is involved in DNA replication at telomeres. Patients with Cockayne syndrome and the closely related Xeroderma Pigmentosum show defects in nucleotide excision repair. This repair pathway removes a variety of DNA lesions and is the major cellular defence mechanism against UV-induced skin cancers.
X-ray crystallography combined with biochemical and biophysical techniques will be used to elucidate the structure and molecular workings of the Werner protein and the Xeroderma Pigmentosum/ Cockayne syndrome protein complexes. The results of these studies are expected to improve our understanding of the machinery that simultaneously provides protection against genomic instability and accelerated aging.
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