Telomerase: A Eukaryotic DNA Polymerase Specialized in Telomeric Repeat Synthesis

Abstract

Telomerase is an RNA-dependent DNA polymerase (reverse transcriptase) specialized in the synthesis of short DNA repeats onto chromosome ends, a function essential for chromosome stability and cellular immortality in eukaryotes. Unlike conventional polymerases, telomerase is a ribonucleoprotein (RNP) enzyme, minimally composed of the catalytic telomerase reverse transcriptase (TERT) and the telomerase RNA (TR) subunit. While the TERT catalytic core is well conserved and shares several motifs with conventional reverse transcriptases, the TR subunit is highly divergent and has evolved species-specific structural elements essential for telomerase RNP assembly and biogenesis. Telomerase is unique among polymerases, capable of producing a DNA product vastly longer than the RNA template. This unique polymerization reaction relies on repeatedly regenerating and reusing the short TR template during DNA synthesis, producing the characteristic repetitive telomeric DNA sequence. Processive telomeric repeat synthesis is dependent on ``template translocation{''} for template regeneration, a complex mechanism that is only partially understood. Correspondingly, telomerase-specific domains within telomerase TERT-TR core function cooperatively with telomerase accessory proteins to coordinate template translocation during processive telomeric DNA repeat synthesis. Telomerase is thus a fascinating polymerase, singular in function and unrivaled in complexity.