Research Paper Volume 13, Issue 13 pp 16957—16973

The dual distinct role of telomerase in repression of senescence and myofibroblast differentiation

Summary cartoon. The findings from the study confirmed the importance of NAD+ dependent Sirt1 in regulation of TERT expression in fibroblasts, which was suppressed by the cellular senescence inducing agents, BLM and H2O2. This suppression was due apparently to depletion of NAD+ since it was reversed by NMN supplementation to increase intracellular NAD+ upon conversion by nicotinamide nucleotide adenylyltransferase (NMNAT). Elevated TERT expression such as in BJ5ta fibroblasts, potently inhibited ACTA2 and CDKN2A gene expression, with evidence of its direct binding to the CDKN2A but not the ACTA2 promoter. TERT inhibition of ACTA2 expression, did not depend on CDKN2A, suggesting that TERT regulation of myofibroblast differentiation was independent of its effects on senescence. YB-1, a known suppressor of both CDKN2A and ACTA2 expression, exhibited binding interactions to the promoters of both genes. Additionally or alternatively, it might interact with TERT to inhibit ACTA2, however inhibition by TERT could not be overcome by depletion of YB-1.

Figure 8. Summary cartoon. The findings from the study confirmed the importance of NAD+ dependent Sirt1 in regulation of TERT expression in fibroblasts, which was suppressed by the cellular senescence inducing agents, BLM and H2O2. This suppression was due apparently to depletion of NAD+ since it was reversed by NMN supplementation to increase intracellular NAD+ upon conversion by nicotinamide nucleotide adenylyltransferase (NMNAT). Elevated TERT expression such as in BJ5ta fibroblasts, potently inhibited ACTA2 and CDKN2A gene expression, with evidence of its direct binding to the CDKN2A but not the ACTA2 promoter. TERT inhibition of ACTA2 expression, did not depend on CDKN2A, suggesting that TERT regulation of myofibroblast differentiation was independent of its effects on senescence. YB-1, a known suppressor of both CDKN2A and ACTA2 expression, exhibited binding interactions to the promoters of both genes. Additionally or alternatively, it might interact with TERT to inhibit ACTA2, however inhibition by TERT could not be overcome by depletion of YB-1.