DNA helicases in genome maintenance: from molecular and cellular mechanisms to specific inhibitors as potential drugs

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Helicases are ubiquitous enzymes, found in viruses, Bacteria, Archaea and eukaryotic cells. They act as motor proteins to separate or remodel DNA or RNA duplexes, using ATP as an energy source. Helicases play a key role in a variety of cellular processes, including DNA replication/repair/recombination, as well as RNA translation and transport. They are emerging as an important class of targets for antiviral, antibiotic and anti-cancer drugs. To date, several genetic and biochemical studies have revealed the molecular and physiological functions of DNA helicases. Moreover, protein three-dimension structural studies coupled with single molecule biophysical approaches have provided insights into structure-function relationships and reaction mechanisms of some key DNA helicases. With a consortium including experts with complementary competence and expertise in Physics, Chemistry, Biology and Clinical Oncology, and a strong commitment of companies involved in drug discovery or in the development of state-of-the-art biophysical instrumentation, we aim to: 1. obtain a detailed picture of the mechanism of action and the physiological role of a number of DNA helicases that are implicated in human diseases; 2. discover specific inhibitors of those enzymes, which can then be tested as novel therapeutic drugs, especially for cancers; 3. address the need for training next generation scientists with complementary approaches and diverse techniques by secondments in different laboratories of the consortium; 4. promote a culture of collaboration between academic and private sectors and provide young scientists with the necessary experience and skills to exploit the full potential of research findings; 5. provide early stage researchers with greater opportunities to access an increasingly competitive job market; 6. promote the values of Open Science and educate young scientists on the importance of a culture of openness, transparency, accessibility, integrity and reproducibility.