A cascade leading to premature aging phenotypes including abnormal tumor profiles in Werner syndrome (review)
Abstract
This perspective review focused on the Werner syndrome (WS) by addressing the issue of how a single mutation in a WRN gene encoding WRN DNA helicase induces a wide range of premature aging phenotypes accompanied by an abnormal pattern of tumors. The key event caused by WRN gene mutation is the dysfunction of telomeres. Studies on normal aging have identified a molecular circuit in which the dysfunction of telomeres caused by cellular aging activates the TP53 gene. The resultant p53 suppresses cell growth and induces a shorter cellular lifespan, and also compromises mitochondrial biogenesis leading to the overproduction of reactive oxygen species (ROS) causing multiple aging phenotypes. As an analogy of the mechanism in natural aging, we described a hypothetical mechanism of premature aging in WS: telomere dysfunction induced by WRN mutation causes multiple premature aging phenotypes of WS, including shortened cellular lifespan and inflammation induced by ROS, such as diabetes mellitus. This model also explains the relatively late onset of the disorder, at approximately age 20. Telomere dysfunction in WS is closely correlated with abnormality in tumorigenesis. Thus, the majority of wide and complex pathological phenotypes of WS ...Continue Reading
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