Abstract A60: Role of telomere dysfunction in the premature cellular senescence of Hutchinson-Gilford progeria syndrome

Abstract

Abstract Introduction: Telomere dysfunction promotes genomic instability and is often associated with loss of tumor suppressor gene function and tumorigenesis. Conversely, in aging, telomere dysfunction is hypothesized to mediate cellular senescence by activating intact tumor suppressor pathways. Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging syndrome caused by a dominant mutation in the nuclear lamina intermediate filament protein lamin A that leads to a truncated and permanently farnesylated protein termed progerin. Progerin expression is associated with early cellular senescence involving shortened telomeres and increased DNA damage. Herein, we investigated whether telomere dysfunction contributes to the DNA damage accumulation and premature cellular senescence phenotypes observed with cells from HGPS patients. Methods: Using HGPS cell lines from patients or normal fibroblasts ectopically expressing progerin, we investigated the effects of telomerase on cell growth, senescence, p53 and Rb tumor suppressor pathway activation, and DNA damage. We also determined whether progerin-induced DNA damage localized to telomeres. Results: We demonstrate that addition of telomerase, which has been reported to immortalize HGPS fibroblasts, abrogated premature senescence, reduced p53 and Rb tumor suppressor pathway activation, and decreased the DNA damage phenotype. These effects of telomerase required both its catalytic and DNA binding activities. Furthermore, progerin-DNA damage signaling localized to telomeres indicating that progerin causes damage at telomeres. Conclusions: These results establish that progerin causes a defect in telomere maintenance linked to a chronic DNA damage response that activates tumor suppressor genes and induces the HGPS premature senescence phenotype. Citation Information: Cancer Res 2009;69(23 Suppl):A60.