Abstract
Fibroblasts derived from glucose-6-phosphate dehydrogenase (G6PD)-deficient patients display retarded growth and accelerated cellular senescence that is attributable to increased accumulation of oxidative DNA damage and increased sensitivity to oxidant-induced senescence, but not to accelerated telomere attrition. Here, we show that ectopic expression of hTERT stimulates telomerase activity and prevents accelerated senescence in G6PD-deficient cells. Stable clones derived from hTERT-expressing normal and G6PD-deficient fibroblasts have normal karyotypes, and display no sign of senescence beyond 145 and 105 passages, respectively. Activation of telomerase, however, does not prevent telomere attrition in earlier-passage cells, but does stabilize telomere lengths at later passages. In addition, we provide evidence that ectopic expression of hTERT attenuates the increased sensitivity of G6PD-deficient fibroblasts to oxidant-induced senescence. These results suggest that ectopic expression of hTERT, in addition to acting in telomere length maintenance by activating telomerase, also functions in regulating senescence induction.
Highlights
Normal human cells grown in vitro replicate for a limited period of time before entering senescence [1], a term that has been used primarily to describe a signal transduction pathway that leads to the irreversible growth arrest of cells in culture
Ectopic expression of hTERT immortalizes fibroblasts derived from normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient patients To address the relative role of oxidative stress and telomere attrition in cellular senescence, we asked whether ectopic expression of hTERT might be capable of restoring telomerase activity and extending the lifespan of G6PDdeficient fibroblasts
We found that ectopic expression of hTERT prevented the accelerated senescence of G6PD-deficient cells and led to their immortalization (Fig. 2)
Summary
Normal human cells grown in vitro replicate for a limited period of time before entering senescence [1], a term that has been used primarily to describe a signal transduction pathway that leads to the irreversible growth arrest of cells in culture. Activation of telomere length-maintenance mechanisms, such as expression of telomerase, a specialized reverse transcriptase that synthesizes telomeric DNA repeats at chromosome ends, is thought to counteract replicative senescence [5,10,11]. In support of this postulate, normal human somatic cells express low or undetectable telomerase activity and are mortal. Ectopic expression of telomerase has been shown to extend the lifespan of many normal human cells cultured in vitro [14,15,16]
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