S E Hamilton1, C G Simmons, I S Kathiriya, D R Corey. 1. Howard Hughes Medical Institute Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75235-9050, USA.
Abstract
BACKGROUND: Human telomerase has an essential RNA component and is an ideal target for developing rules correlating oligonucleotide chemistry with disruption of biological function. Similarly, peptide nucleic acids (PNAs), DNA analogs that bind complementary sequences with high affinity, are outstanding candidates for inducing phenotypic changes through hybridization. RESULTS: We identify PNAs directed to nontemplate regions of the telomerase RNA that can overcome RNA secondary structure and inhibit telomerase by intercepting the RNA component prior to holoenzyme assembly. Relative potencies of inhibition delineate putative structural domains. We describe a novel protocol for introducing PNAs into eukaryotic cells and report efficient inhibition of cellular telomerase by PNAs. CONCLUSIONS: PNAs directed to nontemplate regions are a new class of telomerase inhibitor and may contribute to the development of novel antiproliferative agents. The dependence of inhibition by nontemplate-directed PNAs on target sequence suggests that PNAs have great potential for mapping nucleic acid structure and predictably regulating biological processes. Our simple method for introducing PNAs into cells will not only be useful for probing the complex biology surrounding telomere length maintenance but can be broadly applied for controlling gene expression and functional genomics.
BACKGROUND:Human telomerase has an essential RNA component and is an ideal target for developing rules correlating oligonucleotide chemistry with disruption of biological function. Similarly, peptide nucleic acids (PNAs), DNA analogs that bind complementary sequences with high affinity, are outstanding candidates for inducing phenotypic changes through hybridization. RESULTS: We identify PNAs directed to nontemplate regions of the telomerase RNA that can overcome RNA secondary structure and inhibit telomerase by intercepting the RNA component prior to holoenzyme assembly. Relative potencies of inhibition delineate putative structural domains. We describe a novel protocol for introducing PNAs into eukaryotic cells and report efficient inhibition of cellular telomerase by PNAs. CONCLUSIONS: PNAs directed to nontemplate regions are a new class of telomerase inhibitor and may contribute to the development of novel antiproliferative agents. The dependence of inhibition by nontemplate-directed PNAs on target sequence suggests that PNAs have great potential for mapping nucleic acid structure and predictably regulating biological processes. Our simple method for introducing PNAs into cells will not only be useful for probing the complex biology surrounding telomere length maintenance but can be broadly applied for controlling gene expression and functional genomics.
Authors: V M Tesmer; L P Ford; S E Holt; B C Frank; X Yi; D L Aisner; M Ouellette; J W Shay; W E Wright Journal: Mol Cell Biol Date: 1999-09 Impact factor: 4.272
Authors: Zeyu Lu; Brenton R Paolella; Nicholas L Truex; Alexander R Loftis; Xiaoli Liao; Amy E Rabideau; Meredith S Brown; John Busanovich; Rameen Beroukhim; Bradley L Pentelute Journal: ACS Chem Biol Date: 2020-05-11 Impact factor: 5.100
Authors: B Herbert; A E Pitts; S I Baker; S E Hamilton; W E Wright; J W Shay; D R Corey Journal: Proc Natl Acad Sci U S A Date: 1999-12-07 Impact factor: 11.205