How DNA damage and non-canonical nucleotides alter the telomerase catalytic cycle

Telomeres at the ends of linear chromosomes are essential for genome maintenance and sustained cellular proliferation, but shorten with each cell division. Telomerase, a specialized reverse transcriptase with its own integral RNA template, compensates for this by lengthening the telomeric 3' single strand overhang. Mammalian telomerase has the unique ability to processively synthesize multiple GGTTAG repeats, by translocating along its product and reiteratively copying the RNA template, termed repeat addition processivity (RAP). This unusual form of processivity is distinct from the nucleotide addition processivity (NAP) shared by all other DNA poly-merases. In this review, we focus on the minimally active human telomerase catalytic core consisting of the telomerase reverse transcriptase (TERT) and the integral RNA (TR), which catalyzes DNA synthesis. We review the mechanisms by which oxidatively damaged nucleotides, and anti-viral and anti-cancer nucleotide drugs affect the telomerase catalytic cycle. Finally, we offer perspective on how we can leverage telomerase's unique properties, and advancements in understanding of telomerase catalytic mechanism, to selectively manipulate telomerase activity with therapeutics, particularly in cancer treatment.

Automated summary

Telomeres at the ends of linear chromosomes are essential for genome maintenance and cellular proliferation, but shorten with each cell division. Telomerase compensates for this by lengthening the telomeric 3' single strand overhang, and has the unique ability to synthesize multiple GGTTAG repeats in a process called repeat addition processivity. Understanding telomerase's unique properties and catalytic mechanism may help in selectively manipulating telomerase activity for therapeutic purposes, particularly in cancer treatment.