Transient induction of telomerase expression mediates senescence and reduces tumorigenesis in primary fibroblasts

Abstract

Telomerase is an enzymatic ribonucleoprotein complex that acts as a reverse transcriptase in the elongation of telomeres. Telomerase activity is well documented in embryonic stem cells and the vast majority of tumor cells, but its role in somatic cells remains to be understood. Here, we report an unexpected function of telomerase during cellular senescence and tumorigenesis. We crossed <i>Tert</i> heterozygous knockout mice (<i>mTert</i>^<i>+/-</i> ) for 26 generations, during which time there was progressive shortening of telomeres, and obtained primary skin fibroblasts from <i>mTert</i>^<i>+/+</i> and <i>mTert</i>^<i>-/-</i> progeny of the 26th cross. As a consequence of insufficient telomerase activities in prior generations, both <i>mTert</i>^<i>+/+</i> and <i>mTert</i>^<i>-/-</i> fibroblasts showed comparable and extremely short telomere length. However, <i>mTert</i>^<i>-/-</i> cells approached cellular senescence faster and exhibited a significantly higher rate of malignant transformation than <i>mTert</i>^<i>+/+</i> cells. Furthermore, an evident up-regulation of telomerase reverse-transcriptase (TERT) expression was detected in <i>mTert</i>^<i>+/+</i> cells at the presenescence stage. Moreover, removal or down-regulation of TERT expression in <i>mTert</i>^<i>+/+</i> and human primary fibroblast cells via CRISPR/Cas9 or shRNA recapitulated <i>mTert</i>^<i>-/-</i> phenotypes of accelerated senescence and transformation, and overexpression of TERT in <i>mTert</i>^<i>-/-</i> cells rescued these phenotypes. Taking these data together, this study suggests that TERT has a previously underappreciated, protective role in buffering senescence stresses due to short, dysfunctional telomeres, and preventing malignant transformation.