Chimeric bifunctional oligonucleotides as a novel tool to invade telomerase assembly

被引：8
作者：
Azhibek, Dulat [1 ,2 ,3 ]
Zvereva, Maria [1 ,2 ]
Zatsepin, Timofei [1 ,2 ,3 ]
Rubtsova, Maria [1 ,2 ]
Dontsova, Olga [1 ,2 ]
机构：
[1] Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia
[2] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119992, Russia
[3] Skolkovo Inst Sci & Technol, Odintsovsky Dist 143025, Moscow Region, Russia
来源：
NUCLEIC ACIDS RESEARCH | 2014年 / 42卷 / 15期
基金：
俄罗斯科学基金会;
关键词：
REVERSE-TRANSCRIPTASE; CATALYTIC SUBUNIT; DNA-SYNTHESIS; RNA; INHIBITION; CANCER; CELLS; SEQUENCE; REQUIRES; PROBES;
D O I：
10.1093/nar/gku688
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Telomerase is a key participant in the telomere length maintaining system in eukaryotic cells. Telomerase RNA and protein reverse transcriptase subunits are essential for the appearance of active telomerase in vitro. Telomerase is active in many cancer types and is a potential target for anticancer drug development. Here we report a new approach for impairing telomerase function at the stage of human telomerase assembly. The approach is based on the application of chimeric bifunctional oligonucleotides that contain two oligonucleotide parts complementary to the functional domains of telomerase RNA connected with non-nucleotide linkers in different orientations (5'-3', 5'-5' or 3'-3'). Such chimeras inhibited telomerase in vitro in the nM range, but were effective in vivo in sub-nM concentrations, predominantly due to their effect on telomerase assembly and dimerization.
引用
收藏
页码：9531 / 9542
页数：12
相关论文
共 35 条
  • [11] Telomerase inhibitors - Oligonucleotide phosphoramidates as potential therapeutic agents
    Gryaznov, S
    Pongracz, K
    Matray, T
    Schultz, R
    Pruzan, R
    Aimi, J
    Chin, A
    Harley, C
    Shea-Herbert, B
    Shay, J
    Oshima, Y
    Asai, A
    Yamashita, Y
    [J]. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, 2001, 20 (4-7) : 401 - 410
  • [12] Lipid modification of GRN163, an N3′ → P5′ thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition
    Herbert, BS
    Gellert, GC
    Hochreiter, A
    Pongracz, K
    Wright, WE
    Zielinska, D
    Chin, AC
    Harley, CB
    Shay, JW
    Gryaznov, SM
    [J]. ONCOGENE, 2005, 24 (33) : 5262 - 5268
  • [13] 'Cyclicons' as hybridization-based fluorescent primer-probes: Synthesis, properties and application in real-time PCR
    Kandimalla, ER
    Agrawal, S
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2000, 8 (08) : 1911 - 1916
  • [14] Inhibition of telomerase activity by preventing proper assemblage
    Keppler, BR
    Jarstfer, MB
    [J]. BIOCHEMISTRY, 2004, 43 (02) : 334 - 343
  • [15] Vaults and telomerase share a common subunit, TEP1
    Kickhoefer, VA
    Stephen, AG
    Harrington, L
    Robinson, MO
    Rome, LH
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (46) : 32712 - 32717
  • [16] Reverse transcriptase motifs in the catalytic subunit of telomerase
    Lingner, J
    Hughes, TR
    Shevchenko, A
    Mann, M
    Lundblad, V
    Cech, TR
    [J]. SCIENCE, 1997, 276 (5312) : 561 - 567
  • [17] LNA 5′-phosphoramidites for 5′→3′-oligonucleotide synthesis
    Madsen, Andreas Stahl
    Kumar, T. Santhosh
    Wengel, Jesper
    [J]. ORGANIC & BIOMOLECULAR CHEMISTRY, 2010, 8 (21) : 5012 - 5016
  • [18] Systematic optimization of ion-pairing agents and hexafluoroisopropanol for enhanced electrospray ionization mass spectrometry of oligonucleotides
    McGinnis, A. Cary
    Grubb, E. Claire
    Bartlett, Michael G.
    [J]. RAPID COMMUNICATIONS IN MASS SPECTROMETRY, 2013, 27 (23) : 2655 - 2664
  • [19] Role of telomerase in normal and cancer cells
    Meyerson, M
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2000, 18 (13) : 2626 - 2634
  • [20] Human telomerase activation requires two independent interactions between telomerase RNA and telomerase reverse transcriptase
    Mitchell, JR
    Collins, K
    [J]. MOLECULAR CELL, 2000, 6 (02) : 361 - 371
1234