WRN

Werner syndrome (WS), caused by mutations in WRN, is probably the most dramatic segmental progeroid syndrome. Although there are differences between the pathobiology of normal ageing and the phenotype of WS, the age-related changes of WS patients are remarkably similar to those found during normal ageing, only they occur at earlier ages. WRN is one of the strongest candidates for genes influencing human ageing. WRN-deficient mice display reduced embryonic survival, increased tumour formation, and their fibroblasts show features similar to those found in fibroblasts derived from WS patients such as a premature loss of proliferative capacity, though their ageing process appears unaltered. In late-generation mice without TERC, and hence with short telomeres, WRN mutations result in a phenotype resembling accelerated ageing somewhat reminiscent from WS. WRN is a helicase and exonuclease involved in many DNA repair and processing pathways. Genetic variation studies in breast cancer patients, showed that WRN might have an important tumorigenic role. Human WRN-null mesenchymal stem cells show several features associated with accelerated aging. These include increased senescence associated markers, activation of the senescence-associated secretory phenotype and an increased DNA damage response. In addition, there is a global loss of H3K9me3 and accompanying changes in heterochromatin architecture. It was shown that WRN associates with heterochromatin proteins SUV39H1 and HP1a and nuclear lamina-heterochromatin anchoring protein LAP2b. Thus, WRN may play a role in maintaining heterochromatin stability as part of its role in the ageing process.