The biogenesis and regulation of telomerase holoenzymes

Abstract

Telomerase is an essential eukaryotic reverse transcriptase that is devoted to balancing the net length of the telomeric repeat tracts at chromosome ends. Telomerase is distinct as a polymerase in its dependence on integral protein and RNA subunits, both of which establish the biochemical properties of enzyme activity. Telomerase ribonucleoproteins are endogenously assembled in step-wise pathways under the direction of chaperones. Ribonucleoprotein stability requires species-specific RNA-binding proteins that fold, protect and traffic the telomerase RNA. Telomerase activity at chromosome ends is dependent on proteins that join the stable telomerase ribonucleoprotein to form a catalytically active and telomere-enabled telomerase holoenzyme. How telomerase-associated proteins and structural changes in telomeric chromatin cooperate to determine the extent of repeat synthesis is an interesting open question. The assembly and regulation of telomerase holoenzymes seems to be highly dynamic. Changes in the subcellular distribution of enzyme subunits, their assembly and their access to DNA occur across the cell cycle and also vary with cell type. Numerous known and unknown associated proteins are likely to modulate telomerase assembly and regulation in vivo, and their identification could provide insights into the physiological significance of telomerase dynamics. To accomplish accurate and efficient telomeric repeat synthesis, protein–RNA, protein–DNA and RNA–DNA interactions must be coordinated through the progression of a multi-step telomerase catalytic cycle. Insights into telomerase structure and mechanism are just beginning to provide a picture of the complex engineering that governs template and substrate access to the active site.