Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Nucleic Acids Res. 2002 Jan 15;30(2):559-68.

Allosteric inhibitors of telomerase: oligonucleotide N3'-->P5' phosphoramidates.

Author information

  • 1Geron Corporation, 230 Constitution Drive, Menlo Park, CA 94025, USA. rpruzan@geron.com

Abstract

Telomerase is a ribonucleoprotein responsible for maintaining telomeres in nearly all eukaryotic cells. The enzyme is able to utilize a short segment of its RNA subunit as the template for the reverse transcription of d(TTAGGG) repeats onto the ends of human chromosomes. Transfection with telomerase was shown to confer immortality on several types of human cells. Moreover, telomerase activation appears to be one of the key events required for malignant transformation of normal cells. Inhibition of telomerase activity in transformed cells results in the cessation of cell proliferation in cultures and provides the rationale for the selection of telomerase as a target for anticancer therapy. Using oligonucleotide N3'-->P5' phosphoramidates (NPs) we have identified a region of the human telomerase RNA subunit (hTR) approximately 100 nt downstream from the template region whose structural integrity appears crucial for telomerase enzymatic activity. The oligonucleotides targeted to this segment of hTR are potent and specific inhibitors of telomerase activity in biochemical assays. Mutant telomerase, in which 3 nt of hTR were not complementary to a 15 nt NP, was found to be refractory to inhibition by that oligonucleotide. We also demonstrated that the binding of NP, oligonucleotides to this hTR allosteric site results in a marked decrease in the affinity of a telomerase substrate (single-stranded DNA primer) for the enzyme.

PMID:
11788719
[PubMed - indexed for MEDLINE]
PMCID:
PMC99832
Free PMC Article

Images from this publication.See all images (6)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk