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

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 optim...

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Published in:Nucleic acids research 2015-09, Vol.43 (15), p.e99-e99
Main Authors: Kellermann, Guillaume, Kaiser, Markus, Dingli, Florent, Lahuna, Olivier, Naud-Martin, Delphine, Mahuteau-Betzer, Florence, Loew, Damarys, Ségal-Bendirdjian, Evelyne, Teulade-Fichou, Marie-Paule, Bombard, Sophie
Format: Article
Language:English
Subjects:
Acridines - chemistry
Acridines - pharmacology
Genetic Techniques
HEK293 Cells
Humans
Methods Online
Recombinant Fusion Proteins - biosynthesis
Recombinant Fusion Proteins - isolation & purification
Recombinant Fusion Proteins - metabolism
RNA - chemistry
RNA - metabolism
RNA Folding
Small Molecule Libraries
Structure-Activity Relationship
Telomerase - antagonists & inhibitors
Telomerase - biosynthesis
Telomerase - chemistry
Telomerase - genetics
Telomerase - metabolism
Trisaccharides - chemistry
Trisaccharides - pharmacology
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkv425