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Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression.

Ekta Khattar, Pavanish Kumar, Chia Yi Liu

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    Telomerase reverse transcriptase (TERT) promotes cancer cell proliferation by regulating protein synthesis, independent of its telomere maintenance function. TERT enhances RNA polymerase III activity and tRNA expression, crucial for cancer growth.

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    Area of Science:

    • Molecular Biology
    • Cancer Research
    • Genetics

    Background:

    • Transcriptional reactivation of telomerase reverse transcriptase (TERT) is common in human cancers, typically associated with telomere maintenance.
    • The precise mechanisms by which TERT influences cancer cell proliferation beyond telomere length regulation remain incompletely understood.

    Purpose of the Study:

    • To investigate the telomere-independent functions of TERT in cancer cell proliferation.
    • To elucidate the molecular mechanisms by which TERT regulates cancer cell growth.

    Main Methods:

    • Assessing the impact of TERT expression levels on cancer cell proliferation and telomere length.
    • Genome-wide TERT binding analysis in cancer and embryonic stem cell lines.
    • Investigating the interaction of TERT with RNA polymerase III (pol III) and its effect on tRNA expression.
    • Utilizing TERT-deficient mouse models for tumorigenesis studies.
    • Analyzing TERT and tRNA levels in human cancer samples.

    Main Results:

    • TERT expression enhances cancer cell proliferation independently of telomere length.
    • TERT directly regulates global protein synthesis by associating with the RPC32 subunit of RNA pol III, increasing its recruitment to chromatin and boosting tRNA expression.
    • TERT-deficient mice showed delayed mammary tumorigenesis and increased survival.
    • Restoring RPC32 or TERT expression rescued proliferation defects in TERT-depleted cells.
    • TERT and tRNA levels positively correlated in breast and liver cancer patient samples.

    Conclusions:

    • TERT plays a critical role in cancer cell proliferation through a mechanism that enhances global protein synthesis via RNA pol III and tRNA expression.
    • This telomere-independent function of TERT represents a unifying mechanism driving cancer growth.
    • TERT's role in regulating translation offers potential new therapeutic strategies for cancer treatment.