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Nucleic Acids Res. 2015 Sep 3;43(15):e99. doi: 10.1093/nar/gkv425. Epub 2015 May 9.

Identification of human telomerase assembly inhibitors enabled by a novel method to produce hTERT.

Author information

1
INSERM UMR-S 1007, Cellular Homeostasis and Cancer, Paris, France Université Paris Descartes, Paris Sorbonne Cité, Paris, France guikell@gmail.com.
2
Institut Curie, CMIB, CNRS UMR 9187- INSERM U1196, Orsay, France.
3
Institut Curie/laboratoire de spectrométrie de masse protéomique, Paris, France.
4
INSERM U-1016, Institut Cochin, Paris, France.
5
INSERM UMR-S 1007, Cellular Homeostasis and Cancer, Paris, France Université Paris Descartes, Paris Sorbonne Cité, Paris, France.

Abstract

Telomerase is the enzyme that maintains the length of telomeres. It is minimally constituted of two components: a core reverse transcriptase protein (hTERT) and an RNA (hTR). Despite its significance as an almost universal cancer target, the understanding of the structure of telomerase and the optimization of specific inhibitors have been hampered by the limited amount of enzyme available. Here, we present a breakthrough method to produce unprecedented amounts of recombinant hTERT and to reconstitute human telomerase with purified components. This system provides a decisive tool to identify regulators of the assembly of this ribonucleoprotein complex. It also enables the large-scale screening of small-molecules capable to interfere with telomerase assembly. Indeed, it has allowed us to identify a compound that inhibits telomerase activity when added prior to the assembly of the enzyme, while it has no effect on an already assembled telomerase. Therefore, the novel system presented here may accelerate the understanding of human telomerase assembly and facilitate the discovery of potent and mechanistically unique inhibitors.

PMID:
25958399
PMCID:
PMC4551907
DOI:
10.1093/nar/gkv425
[Indexed for MEDLINE]
Free PMC Article

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