A model for the phenotypic presentation of Werner's syndrome.
Werner's syndrome (WS) is a valuable model of accelerated ageing and results from mutations in a recQ helicase (wrn). WS fibroblasts show a mutator phenotype, replication fork stalling, increased rates of mean telomeric loss and accelerated cellular senescence. Senescence has been proposed as a candidate mechanism for the ageing of mitotic tissue. However, some mitotic tissues (such as the immune system) seem unaffected in WS. Is this evidence against a role for cell senescence in ageing? Two experiments resolve this paradox (i) the demonstration that the abbreviated replicative lifespan of WS fibroblasts can be corrected by the ectopic expression of telomerase and (ii) the demonstration that T cells derived from WS patients have the mutator phenotype characteristic of the disease but show no reduction in replicative potential. Since T cells can upregulate telomerase naturally these findings are consistent with a model in which the only wrn-mediated deletions that have a significant effect on replicative lifespan are those at or near the telomere. These data are thus supportive of a role for senescence in the ageing of the immune system. Emerging data on divisional counting mechanisms have the potential to produce many other apparent WS "paradoxes". Accordingly, we propose a general model for the phenotypic presentation of WS, which includes a modification of the Olovnikov model of telomere erosion. Somewhat unexpectedly, this predicts that accelerated senescence should not be observed in all telomerase-negative WS cell types.
Ostler
E L
EL
School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Brighton, East Sussex BN2 4GJ, UK.
Wallis
C V
CV
Sheerin
A N
AN
Faragher
R G A
RG
D000375:Aging / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000818:Animals; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D004265:DNA Helicases / Q000235:genetics; D005090:Exodeoxyribonucleases; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D010641:Phenotype; D053484:RecQ Helicases; D014898:Werner Syndrome / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D000071657:Werner Syndrome Helicase
D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase