TY - JOUR
T1 - Inhibition of human telomerase by 2′-O-methyl-RNA
AU - Pitts, A. E.
AU - Corey, D. R.
PY - 1998/9/29
Y1 - 1998/9/29
N2 - Telomerase, a ribonucleoprotein up-regulated in many types of cancers, possesses an RNA template necessary to bind and extend telomere ends. The intrinsic accessibility of telomerase to incoming nucleic acids makes the RNA template an ideal target for inhibition by oligonucleotides. We report here that 2′-O-methyl-RNA (2′-O-meRNA), an oligonucleotide chemistry known to exert sequence-specific effects in cell culture and animals, inhibits lelomerase with potencies superior to those possessed by analogous peptide nucleic acids (PNAs). Potent inhibition relative to PNAs is surprising, because the binding affinity of 2′-O-meRNAs for complementary RNA is low relative to analogous PNAs. A 2′-O-meRNA oligomer with terminal phosphorothioate substitutions inhibits telomerase sequence-selectively within human-tumor-derived DU145 cells when delivered with cationic lipids. In contrast to the ability of 2′-O-meRNA oligomers to inhibit telomerase, the binding of a 2′-O-meRNA to an inverted repeat within plasmid DNA was not detectable, whereas binding of PNA was efficient, suggesting that the relative accessibility of the telomerase RNA template is essential for inhibition by 2′-O-meRNA. Inhibition of telomerase by 2′-O-meRNA will facilitate probing the link between telomerase activity and sustained cell proliferation and may provide a basis for the development of chemopreventive and chemotherapeutic agents.
AB - Telomerase, a ribonucleoprotein up-regulated in many types of cancers, possesses an RNA template necessary to bind and extend telomere ends. The intrinsic accessibility of telomerase to incoming nucleic acids makes the RNA template an ideal target for inhibition by oligonucleotides. We report here that 2′-O-methyl-RNA (2′-O-meRNA), an oligonucleotide chemistry known to exert sequence-specific effects in cell culture and animals, inhibits lelomerase with potencies superior to those possessed by analogous peptide nucleic acids (PNAs). Potent inhibition relative to PNAs is surprising, because the binding affinity of 2′-O-meRNAs for complementary RNA is low relative to analogous PNAs. A 2′-O-meRNA oligomer with terminal phosphorothioate substitutions inhibits telomerase sequence-selectively within human-tumor-derived DU145 cells when delivered with cationic lipids. In contrast to the ability of 2′-O-meRNA oligomers to inhibit telomerase, the binding of a 2′-O-meRNA to an inverted repeat within plasmid DNA was not detectable, whereas binding of PNA was efficient, suggesting that the relative accessibility of the telomerase RNA template is essential for inhibition by 2′-O-meRNA. Inhibition of telomerase by 2′-O-meRNA will facilitate probing the link between telomerase activity and sustained cell proliferation and may provide a basis for the development of chemopreventive and chemotherapeutic agents.
UR - http://www.scopus.com/inward/record.url?scp=0032578525&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032578525&partnerID=8YFLogxK
U2 - 10.1073/pnas.95.20.11549
DO - 10.1073/pnas.95.20.11549
M3 - Article
C2 - 9751703
AN - SCOPUS:0032578525
SN - 0027-8424
VL - 95
SP - 11549
EP - 11554
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -