The protein subunit of telomerase displays patterns of dynamic evolution and conservation across different metazoan taxa

Abstract

BackgroundMost animals employ telomerase, which consists of a catalytic subunit known as the telomerase reverse transcriptase (TERT) and an RNA template, to maintain telomere ends. Given the importance of TERT and telomere biology in core metazoan life history traits, like ageing and the control of somatic cell proliferation, we hypothesised that TERT would have patterns of sequence and regulatory evolution reflecting the diverse life histories across the Animal Kingdom.ResultsWe performed a complete investigation of the evolutionary history of TERT across animals. We show that although TERT is almost ubiquitous across Metazoa, it has undergone substantial sequence evolution within canonical motifs. Beyond the known canonical motifs, we also identify and compare regions that are highly variable between lineages, but show conservation within phyla. Recent data have highlighted the importance of alternative splice forms of TERT in non-canonical functions and although animals may share some conserved introns, we find that the selection of exons for alternative splicing appears to be highly variable, and regulation by alternative splicing appears to be a very dynamic feature of TERT evolution. We show that even within a closely related group of triclad flatworms, where alternative splicing of TERT was previously correlated with reproductive strategy, we observe highly diverse splicing patterns.ConclusionsOur work establishes that the evolutionary history and structural evolution of TERT involves previously unappreciated levels of change and the emergence of lineage specific motifs. The sequence conservation we describe within phyla suggests that these new motifs likely serve essential biological functions of TERT, which along with changes in splicing, underpin diverse functions of TERT important for animal life histories.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-017-0949-4) contains supplementary material, which is available to authorized users.

Structure ofS. pombetelomerase protein Pof8 C-terminal domain is an xRRM conserved among LARP7 proteins

“…Single residue substitutions Y330A (RNP3) and R343A (b3) had similarly deleterious 24 effects in vivo compared to deletion of helix a3, deletion of the RRM, or full-length knock-down 25 (16), consistent with their predicted importance for nucleotide recognition in the putative Pof8 26 RNA binding pocket (Fig 5D). 27 In p65 and hLarp7, the binding pocket recognizes two or three nucleotides, respectively, 1 that insert into the binding pocket between helix a3 and b3-b2, one of which is a Gua (Fig 5G). 2…”

TERTgene: its function and dysregulation in cancer

“…The protein product TERT exists as a dimer within the telomerase holoenzyme14 and consists of three regions: (1) the N-terminal extension that contains an N-terminal domain and a telomerase RNA-binding domain; (2) the central catalytic reverse transcriptase domain; and (3) the C-terminal extension 15. This basic organisation has remained remarkably stable over evolutionary time,16 implying that it was present in basal metazoans at the emergence of multicellularity. Interestingly, TERT is not present in Drosophila , as this genus does not use telomerase to solve the end replication problem 17…”

New perspectives on telomerase RNA structure and function

“…The advent of the linear genome presented a challenge to the conventional replication machinery, which requires a RNA primer to initiate synthesis of DNA. Thus, when the replisome approaches the end of a linear DNA molecule, the ends cannot be completely replicated, a situation often termed the ‘end replication problem.’ Most eukaryotes employ a unique reverse transcriptase (RT) in a clever work‐around to this problem . This unique enzyme together with its associated noncoding RNA is called telomerase and adds short DNA repeats to chromosome ends; a simple solution to the end‐replication problem that requires a complex ribonucleoprotein (RNP) enzyme to enact.…”

“…The TERT subunit is highly conserved across species and contains several domains: the telomerase essential N‐terminal (TEN) domain, the telomerase RNA‐binding domain (TRBD), the RT domain, and the C‐terminal extension (CTE) (Figure (b)). Within these domains lie many conserved motifs, for example, the CP and T‐FLY motifs in the TRBD, and the GQ motif in the TEN domain.…”

“…3,4 Most eukaryotes employ a unique reverse transcriptase (RT) in a clever work-around to this problem. 2,5 This unique enzyme together with its associated noncoding RNA is called telomerase and adds short DNA repeats to chromosome ends; a simple solution to the endreplication problem that requires a complex ribonucleoprotein (RNP) enzyme to enact.…”