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miR-128 inhibits telomerase activity by targeting TERT mRNA

Herlinda Guzman, Katie Sanders, Adam Idica, Aurore Bochnakian, Douglas Jury, Iben Daugaard, Dimitrios G Zisoulis, Irene Munk Pedersen
doi: https://doi.org/10.1101/195198
Herlinda Guzman
1Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine, CA 92697-3900.
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Katie Sanders
1Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine, CA 92697-3900.
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Adam Idica
1Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine, CA 92697-3900.
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Aurore Bochnakian
1Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine, CA 92697-3900.
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Douglas Jury
1Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine, CA 92697-3900.
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Iben Daugaard
1Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine, CA 92697-3900.
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Dimitrios G Zisoulis
1Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine, CA 92697-3900.
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Irene Munk Pedersen
1Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine, CA 92697-3900.
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ABSTRACT

Telomerase is a unique cellular reverse transcriptase essential for maintaining telomere stability and required for the unlimited proliferation of cancer cells. The limiting determinant of telomerase activity is the catalytic component TERT, and TERT expression is closely correlated with telomerase activity and cancer initiation and disease progression. For this reason the regulation of TERT levels in the cell is of great importance. microRNAs (miRs) function as an additional regulatory level in cells, crucial for defining expression boundaries, proper cell fate decisions, cell cycle control, genome integrity, cell death and metastasis. We performed an anti-miR library screen to identity novel miRs, which participate in the control of telomerase. We identified the tumor suppressor miR (miR-128) as a novel endogenous telomerase inhibitor and determined that miR-128 significantly reduces the mRNA and protein levels of Tert in a panel of cancer cell lines. We further evaluated the mechanism by which miR-128 regulates TERT and demonstrated that miR-128 interacts directly with the coding sequence of TERT mRNA in both HeLa cells and teratoma cells. Interestingly, the functional miR-128 binding site in TERT mRNA, is conserved between TERT and the other cellular reverse transcriptase encoded by Long Interspaced Elements-1 (LINE-1 or L1), which can also contribute to the oncogenic phenotype of cancer. This finding supports the novel idea that miRs may function in parallel pathways to inhibit tumorigenesis, by regulating a group of enzymes (RT) by targeting conserved binding sites in the coding region of both enzymes.

NOVELTY AND IMPACT Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences and almost universally provides the molecular basis for unlimited proliferative potential. Expression of human telomerase alone is sufficient for the immortalization of diverse cell types. We have identified the tumor suppressor microRNA (miR-128) as a novel regulator of telomerase, which directly targets the coding sequence (CDS) of TERT mRNA and significantly represses Tert protein expression in a panel of cancer cell lines.

  • ABBREVIATIONS

    Ago
    Argonaute
    BMI-1
    BMI1 Proto-Oncogene, Polycomb Ring Finger
    CDS
    coding sequence
    GAPDH
    Glyceraldehyde 3-phosphate dehydrogenase
    GFP
    green fluorescent protein
    iPSC
    induced pluripotent stem cells
    L1 or LINE-1
    long-interspaced element-1
    miR
    microRNA
    miRISC
    miR-induced silencing complex
    mRNA
    messenger RNA
    ORF
    open reading frame
    PUMA
    p53 upregulated modulator of apoptosis
    q-TRAP
    Real-time quantitative telomeric repeat amplification
    RIP
    Argonaute-RNA immuno-purification
    RT
    reverse transcriptase
    SIRT1
    silent mating type information regulation 2 homolog
    shRNA
    short hairpin RNA
    TERT
    Telomerase Reverse Transcriptase
    TERC
    telomerase RNA component
    WT
    wild type
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    Posted October 06, 2017.
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    miR-128 inhibits telomerase activity by targeting TERT mRNA
    Herlinda Guzman, Katie Sanders, Adam Idica, Aurore Bochnakian, Douglas Jury, Iben Daugaard, Dimitrios G Zisoulis, Irene Munk Pedersen
    bioRxiv 195198; doi: https://doi.org/10.1101/195198
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    miR-128 inhibits telomerase activity by targeting TERT mRNA
    Herlinda Guzman, Katie Sanders, Adam Idica, Aurore Bochnakian, Douglas Jury, Iben Daugaard, Dimitrios G Zisoulis, Irene Munk Pedersen
    bioRxiv 195198; doi: https://doi.org/10.1101/195198

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