ROLE OF THE WERNER SYNDROME HELICASE IN GENOME STABILITY

The Werner's syndrome is a rare genetic disease characterised by symptoms of premature aging, such as arteriosclerosis, greying of the hair and cataract and by predisposition to cancer. Cells derived from Werner's syndrome individuals show a reduced proliferative potential in culture, are hypersensitive to certain drugs affecting the duplication of the genome, accumulate chromosome aberrations and mutations in their DNA. In addition, cells from Werner's syndrome present an elevated apoptotic cell death compared to normal cells. The gene mutated in Werner's syndrome encode for a protein called Werner (WRN), which is an helicase, this is an enzyme that unwinds the two helices of the DNA to allow replication, repair and transcription of the genome. Specifically, WRN is a RecQ helicase. RecQ helicases are a family of enzymes that are apparently involved in the controlling the quality of the process of genome duplication, avoiding the accumulation of chromosome rearrangements and mutations, two processes at the basis of tumoral transformation and of the instability of certain sequences that are found in the genome as long tandem repeats of three bases. Instability of these sequences is causative of severe genetic diseases such as Fragile X and Huntington disease.The molecular role of WRN as well as the molecular pathology of the syndrome are still poorly understood and this project has the aim to improve our knowledge about the WRN functions during replication, understanding how WRN contributes to avoid that replication "goes down" and breaks form in the genome. In addition, this project aims to understand whether the syndrome and its clinical features may specifically derive from the loss of WRN caretaker role during DNA replication. The study of the molecular basis of the Werner's syndrome may eventually help in define new diagnostic approaches and in the future help in develop new and preventive therapeutic approaches.