Telomerase reverse transcriptase inhibitor NU-1 enhances radiation and chemotherapy sensitivity

The human telomerase reverse transcriptase, hTERT, is normally expressed in 16 highly proliferative tissue precursors, where it maintains telomere length and 17 supports other non-canonical functions. That hTERT is critical for the proliferation 18 and survival of many cancers has made telomerase an attractive target. Efforts to 19 block telomere elongation with small molecule inhibitors have yet to demonstrate 20 clinical impact, raising the question whether targeting other functions of hTERT 21 might be more effective. We recently reported NU-1, a novel covalent inhibitor 22 derived from the natural product chrolactomycin, that irreversibly blocks the 23 telomerase activity of hTERT. Here, we examine effects of NU-1 on extra-24 telomeric functions of hTERT regulating DNA damage response, proliferation and 25 cellular senescence. While treating telomerase-positive cancer cells with NU-1 26 prior to irradiation delays repair of DNA double stand breaks (DSBs), resulting in 27 persistent DNA damage signaling, no such effects were observed in telomerase-28 negative cancer cells. Our results establish NU-1 as a chemical probe to explore 29 extra-telomeric functions of hTERT and suggest telomerase inhibitors as tumor-30 specific radio/chemo-sensitizers.