Telomeres are a fascinating and essential aspect of linear chromosomal DNA, protecting the ends of the chromosomes from entanglement with other nuclear molecules and from material loss during replication. In brief, they consist of many repetitions of a specific short sequence capped by a knot-like structure. Each time the cell copies a chromosome, the primer-based nature of linear DNA replication means that some of these repeats are lost, eventually leading to cell death when the entire telomere is used up. To prevent this, many cells use the enzyme telomerase to extend the telomere region, using telomerase RNA as the template for the extension.
While a lot of RNA sequencing studies focus on the more well-known protein-coding mRNAs, telomerase RNA is a type of long non-coding RNA that can be difficult to study or predict because neither its sequence nor its size are well-conserved across evolutionary lineages. Additionally, the pathways for generating telomerase RNA within a cell differ between eukaryotic groups, even to the point where different lineages use different RNA polymerase enzymes for transcribing the telomerase RNA.
In their forthcoming publication, “Biogenesis of telomerase RNA from an mRNA precursor”, lead author Dr. Dhenugen Logeswaran and his team describe a previously unknown biogenesis pathway for telomerase RNA, where the telomerase RNA is created from an mRNA that also codes for a functional protein, via alternative splicing. What really stands out to me in their work is the breadth of their bioinformatic analysis – while the paper is fundamentally supported by thorough biochemical research, they used multiple analytic approaches to confirm their hypotheses instead of limiting themselves to a single method, which lends a lot of confidence to their results.
For example, a major part of their paper was confirming that the precursor of this telomerase RNA was a true protein-coding mRNA, which involved showing that the precursor RNA was able to produce a functional protein. To do this, they first showed via multiple local sequence alignment that the precursor mRNA contained conserved consensus sequences with potential homologs in other fungal species and yeast; they then created a phylogeny using those homologous sequences and showed that the evolution of these sequences matched the evolutionary pathway of those fungal and yeast species; and finally they modeled all the potential homologous proteins and found that they had similar structures and conserved domains. To supplement the informatics, they also showed that knocking out the gene for the precursor mRNA caused functional changes as would be expected based on the function of the known homologous proteins (in addition to knocking out telomere extension in the cells).
Telomeres are an important facet of research into both aging and cancer, as both restricted and unconstrained cell growth can have negative ramifications for an organism. By discovering a new pathway by which telomeres can be extended and regulated, Logeswaran is helping to expand the basic knowledge necessary for more translational applications of this science. While I wasn’t involved in the informatics for this publication, it has been my privilege to work with both Dr. Logeswaran and Dr. Chen (also an author on this paper) on other projects, and I am looking forward to seeing what else comes from their lab – as with this paper, their research is characterized by its thorough and well-planned nature.
Citation
Logeswaran, D., Li, Y., Akhter, K., Podlevsky, JD., Olson, TL., Forsberg, K., Chen, JL. “Biogenesis of telomerase RNA from a protein-coding mRNA precursor.” 2022 PNAS, forthcoming.