Telomere length mediates the effects of telomerase on the cellular response to genotoxic stress.
Telomerase inhibition may be a novel anti-cancer strategy that can be used in combination with conventional therapies, such as DNA damaging agents. There are conflicting reports as to whether and to what extent telomerase and telomere length influence the sensitivity of cells to genotoxins. To understand the relationship between telomere length, telomerase expression, and sensitivity to genotoxic stress, we expressed the catalytic subunit of telomerase, hTERT, in human fibroblasts having different telomere lengths. We show that telomerase confers resistance to ionizing radiation, bleomycin, hydrogen peroxide, and etoposide only in cells with short, presumably near-dysfunctional, telomeres. This resistance depended on the ability of telomerase to elongate the short telomeres, and telomerase did not protect cells with long telomeres. Interestingly, although long telomeres had no effect on sensitivity to etoposide and bleomycin, they exacerbated sensitivity to hydrogen peroxide, supporting the idea that, compared to other types of DNA damage, telomeres are particularly vulnerable to oxidative damage. Our findings identify a mechanism and conditions under which telomerase and telomeres affect the response of human cells to genotoxic agents and may have important implications for anti-cancer interventions.
Rubio
Miguel A
MA
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Davalos
Albert R
AR
Campisi
Judith
J
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001761:Bleomycin / Q000494:pharmacology; D020134:Catalytic Domain / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D018014:Gene Transfer Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000235:genetics*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D001761:Bleomycin; D005047:Etoposide; D006861:Hydrogen Peroxide; D019098:Telomerase