Sp1 and Sp3 recruit histone deacetylase to repress transcription of human telomerase reverse transcriptase (hTERT) promoter in normal human somatic cells

  • Won J
  • Yim J
  • Kim T
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Abstract

Activation of telomerase is crucial for cells to gain immortality. In human cells, telomerase activity is tightly regulated by the expression of its catalytic sub-unit, human telomerase reverse transcriptase (hTERT). In most normal human somatic cells, hTERT is not ex-pressed, and its suppression acts as an important gate-keeper against tumorigenesis. Here we describe the sys-tematic analyses of hTERT promoter to understand the transcriptional repression mechanism of the hTERT gene in normal human somatic cells. Through the serial deletion analysis of hTERT promoter in normal human fibroblasts, we identified a critical repressive element on the hTERT promoter. The repressive element formed DNA-protein complexes with Sp1 and Sp3 in nuclear extracts. Using formaldehyde cross-linked chromatin immunoprecipitation analysis, we found that Sp1 and Sp3 were associated with the endogenously repressed hTERT promoter in human fibroblasts. Furthermore, Sp1 and Sp3 interacted with histone deacetylase (HDAC) in these cells. Overexpression of dominant-negative mutants of Sp1 and Sp3, which contained mainly the HDAC2-binding domain, relieved the HDAC-mediated repression of the hTERT promoter. Taken together, these results suggest that Sp1 and Sp3 associate with the hTERT promoter, recruiting HDAC for the localized deacetylation of nu-cleosomal histones and transcriptional silencing of the hTERT gene in normal human somatic cells. All tumor cells have functional telomere stabilization mech-anisms, and most of them employ the enzyme telomerase to achieve this requirement (1–3). By catalyzing the addition of telomeric TTAGGG repeats onto the chromosome ends, telo-merase stabilizes the telomere, and thus maintains the stability and integrity of linear chromosomes. In contrast, most normal human somatic cells lack the mechanisms to maintain

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Authors

  • Jaejoon Won

  • Jeongbin Yim

  • Tae Kook Kim

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