Nature Comm Publication

The Opresko lab celebrated the acceptance of Samantha Sanford’s first author paper for publication in Nature Communications entitled “Therapeutic 6-thio-2”deoxyguanosine inhibits telomere elongation in cancer cells by inducing a non-productive stalled telomerase complex”. This work revealed the mechanism by which the drug 6-thio-dG causes telomere shortening in cancer cells to halt cell proliferation, and was a terrific collaboration with the laboratories of Suneet Agarwal, Mark Hedglin, Sua Myong, and Michael Stone.

Find the abstract and link to article below:

Abstract: Most cancers upregulate the telomere lengthening enzyme telomerase to achieve unlimited cell division. How chemotherapeutic nucleoside 6-thio-2'-deoxyguanosine (6-thio-dG) targets telomerase to inhibit telomere maintenance in cancer cells and tumors was unclear. Here, we demonstrate that telomerase insertion of 6-thio-dGTP prevents synthesis of additional telomeric repeats but does not disrupt telomerase binding to telomeres. Specifically, 6-thio-dG inhibits telomere extension after telomerase translocates along its product DNA to reposition the template, inducing a non-productive complex rather than enzyme dissociation. Furthermore, we provide direct evidence that 6-thio-dG treatment inhibits telomere synthesis by telomerase in cancer cells. In agreement, telomerase-expressing cancer cells harboring critically short telomeres are more sensitive to 6-thio-dG and show a greater induction of telomere losses compared to cancer cells with long telomere reserves. Our studies reveal that telomere length and telomerase status determine 6-thio-dG sensitivity and uncover the molecular mechanism by which 6-thio-dG selectively inhibits telomerase synthesis of telomeric DNA.
https://pubmed.ncbi.nlm.nih.gov/41354720/