Uncovering the molecular pathology of Werner syndrome: analysis of the functional relationship between ATR-related WRN function, replication stress and premature cellular senescence

The Werner syndrome is a rare genetic disease characterized by symptoms of premature aging, such as arteriosclerosis, graying of the hair and cataract and by predisposition to cancer. Cells derived from Werner syndrome show a reduced proliferative potential in culture, are hypersensitive to drugs affecting DNA replication and accumulate chromosome aberrations. In addition, cells from Werner syndrome present an elevated apoptotic cell death compared to normal cells. The gene mutated in Werner syndrome encodes 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 cancer and instability of certain sequences that are found in the genome. How WRN counteracts the premature onset of replicative senescence in vitro and avoids premature ageing in vivo is still poorly understood. One of the mechanism that have been envisaged is correlated to telomeres, those specialized sequences at chromosome ends that become more and more short each round of cellular duplication. Once telomeres are too short to support the faithful duplication of the chromosome ends, cells become senescent. During the previously funded proposal, we showed that WRN is actually one of the most important proteins of a specialized process that avoids accumulation of DNA damage during the duplication of the genome. Since recent reports indicate that that specialized process is also involved in the duplication of telomeres, now we aim to study if the role of WRN in this specialized process is linked to the premature senescence in order to better understand how premature ageing appears in patients affected by WS.