Inducing rapid telomere irreparable damage in telomerase-expressing cancers

Zhang, Gao; Shay, Jerry W.

doi:10.18632/oncotarget.26317

Cited by 1 publication

(1 citation statement)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While studies confirmed that various NRTIs cause telomere shortening and inhibit telomerase in vitro 19 – 21 , whether telomerase can insert these chain-terminating analogs during telomere synthesis was unknown. Thiopurines are another class of therapeutic nucleoside analogs that cause telomere shortening, and are currently used in clinical practice as antileukemic, anti-inflammatory, and immunosuppressive agents 22 – 24 . 6-thio-dGTP, which forms in cells from 6-thio-dG, promotes cell death in telomerase-positive cancer cells but not in normal cells, and decreases tumor growth in mouse xenograft studies 25 .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of telomerase inhibition by oxidized and therapeutic dNTPs

et al. 2020

View full text Add to dashboard Cite

Telomerase is a specialized reverse transcriptase that adds GGTTAG repeats to chromosome ends and is upregulated in most human cancers to enable limitless proliferation. Here, we uncover two distinct mechanisms by which naturally occurring oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation. We conduct a series of direct telomerase extension assays in the presence of modified dNTPs on various telomeric substrates. We provide direct evidence that telomerase can add the nucleotide reverse transcriptase inhibitors ddITP and AZT-TP to the telomeric end, causing chain termination. In contrast, telomerase continues elongation after inserting oxidized 2-OH-dATP or therapeutic 6-thio-dGTP, but insertion disrupts translocation and inhibits further repeat addition. Kinetics reveal that telomerase poorly selects against 6-thio-dGTP, inserting with similar catalytic efficiency as dGTP. Furthermore, telomerase processivity factor POT1-TPP1 fails to restore processive elongation in the presence of inhibitory dNTPs. These findings reveal mechanisms for targeting telomerase with modified dNTPs in cancer therapy.

show abstract