Transient Telomerase Inhibition with Imetelstat Impacts DNA Damage Signals and Cell-Cycle Kinetics

Molecular Cancer Research : MCR
Connor A H ThompsonJudy M Y Wong

Abstract

Telomerase is the ribonucleoprotein reverse transcriptase that catalyzes the synthesis of telomeres at the ends of linear chromosomes and contributes to proper telomere-loop (T-loop) formation. Formation of the T-loop, an obligate step before cell division can proceed, requires the generation of a 3'-overhang on the G-rich strand of telomeric DNA via telomerase or C-strand specific nucleases. Here, it is discovered that telomerase activity is critical for efficient cell-cycle progression using transient chemical inhibition by the telomerase inhibitor, imetelstat. Telomerase inhibition changed cell cycle kinetics and increased the proportion of cells in G2-phase, suggesting delayed clearance through this checkpoint. Investigating the possible contribution of unstructured telomere ends to these cell-cycle distribution changes, it was observed that imetelstat treatment induced γH2AX DNA damage foci in a subset of telomerase-positive cells but not telomerase-negative primary human fibroblasts. Chromatin-immunoprecipitation with γH2AX antibodies demonstrated imetelstat treatment-dependent enrichment of this DNA damage marker at telomeres. Notably, the effects of telomerase inhibition on cell cycle profile alterations were abrogated ...Continue Reading

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Citations

Apr 24, 2019·Cell Biochemistry and Function·Karollyne da Silva MoraisDiêgo Madureira de Oliveira
Oct 18, 2020·Cancers·Chelsea E CunninghamFranco J Vizeacoumar
Mar 13, 2021·Expert Review of Gastroenterology & Hepatology·Liang-Jie TangMing-Hua Zheng
Jun 5, 2021·Nature Communications·Gabrijela DumbovićJohn L Rinn

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