Telomerase and Retrotransposons: Reverse Transcriptases That Shaped Genomes
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Telomerase and retrotransposons: Reverse transcriptases that shaped genomes Marlene Belforta,b,c,1, M. Joan Curciob,c,1, and Neal F. Lued,1 aDepartment of Biological Sciences and RNA Institute, University at Albany, State University of New York, Albany, NY 12222; bWadsworth Center, New York State Department of Health, Albany, NY 12201-2002; cDepartment of Biomedical Sciences, University at Albany, State University of New York, Albany, NY 12222; and dDepartment of Microbiology and Immunology, W. R. Hearst Microbiology Research Center, Weill Medical College of Cornell University, New York, NY 10065 “Two independent groups of investigators while maintaining cellular balance and then the cDNA is inserted into the ge- have found evidence of an enzyme... which genome integrity. nome via integrase (5). synthesizes DNA from an RNA template. The colloquium addressed the evolution This discovery, if upheld, will have impor- and interrelationships of RTs of viruses, Evolutionary Relationships tant implications... information transfer ” transposons, telomeres, and cellular genes, It has been appreciated for some time that from DNA to RNA can be inverted. 1970, telomerase and retrotransposon RTs ex- preamble to refs. 1 and 2. while exploring RT structure, function, and its bearing on development, aging, and hibit a number of structural and mecha- hese words accompanied two disease. It remains debatable whether nistic similarities and are likely to share articles describing the discovery telomerases represent domesticated ret- a common origin (6–11). Phylogenetic Tof RNA-dependent DNA poly- rotransposons or whether these chromo- analyses reinforce a deep-rooted connec- merase, now known as reverse some-capping agents radiated into mobile tion between these two families of poly- transcriptase (RT), in the virions of RNA genetic elements. Nevertheless, their phy- merases (Fig. 1C). Irina Arkhipova’s tumor viruses. RT activity was recognized logenetic and functional relatedness is lecture, as well as the accompanying arti- independently by David Baltimore (1) and clear (Fig. 1), and indeed, retrotrans- cle on a distinct group of RTs (12), ex- Howard Temin and Satoshi Mizutani (2). posons can provide alternative means of plored evolutionary space between the In five printed pages these authors col- maintaining chromosome ends, as will large class of RTs that are associated with fi lectively challenged the unidirectionality become evident from the following. diverse sel sh mobile retroelements and “ of macromolecular synthesis, from DNA The colloquium and this compendium of telomerase RT. She described an evolu- ” to RNA to protein, the central dogma of articles reflect the lifestyle of retroviruses, tionary intermediate, a unique family of molecular biology. Indeed by demonstrat- retrotransposons, and telomeres. The single-copy RT genes that is not only dis- ing that DNA synthesis can be templated retrotransposons we consider are the tinct from the telomerase RT gene but by RNA, they overturned the central retroviral-like elements that contain long also shows none of the hallmarks of mo- dogma. However, there was no way of terminal repeats [LTR retrotransposons bile element association. This RT gene predicting how in the ensuing 4 decades (e.g., Ty elements)] and those that do not family seems to have ancient origins and is found sporadically throughout all eukary- scientists would uncover the essential role contain LTRs [e.g., long interspersed otic kingdoms. Thus, telomerase is not the of RT in shaping genomes and making nuclear elements (LINE) elements and only single-copy gene that evolved from possible the diversity of life on earth. group II introns]. These non-LTR retro- an ancestral RT gene. This finding lends This was the topic of the colloquium transposons are also referred to as target- credence to the idea that different classes “Telomerase and Retrotransposons: Re- primed (TP) elements, for their mecha- of retroelements evolved independently verse Transcriptases that Shaped Ge- nism of chromosome integration (3). The from divergent single-copy RT genes. nomes,” held September 29–30, 2010, architecture of the different retroelements Another connection between telomeres which forms the basis of this special fea- under consideration is schematized in Fig. and retrotransposons was provided ture. We now know that approximately 1A, indicating that they are all molecular fi by Mary-Lou Pardue, who described half of the human genome and a signi - mosaics, with different functional modules Drosophila telomeres, which are main- cant portion of every other eukaryotic associated with RT. RT is fused to pro- tained not by telomerase but rather by re- genome is generated by RTs, which are tease and integrase domains in both ret- peated retrotransposition of a small set of present in two major forms: telomerases, roviruses and LTR retrotransposons, retroelements HeT-A, TART, and TAHRE which synthesize the ends of linear eu- whereas RT is juxtaposed to endonuclease (13). In a “natural” experiment in the karyotic chromosomes, and retrotrans- domains in TP retrotransposons and some poson RTs, which deposit copies of group II introns. Retrotransposition of themselves throughout the genetic land- a TP retrotransposon or group II intron is This paper results from the Arthur M. Sackler Colloquium scape and generate pseudogenes with usually initiated by endonucleolytic cleav- of the National Academy of Sciences, “Telomerase and spectacularly diverse roles in gene regula- age, exposing a 3′-OH that serves as the Retrotransposons: Reverse Transcriptases that Shaped Ge- nomes” held September 29–30, 2010, at the Arnold and tion. There was no inkling 40 years ago primer for reverse transcription, with the Mabel Beckman Center of the National Academies of Sci- that misregulation of RTs can cause RNA of the element being the template ences and Engineering in Irvine, CA. The complete program chromosomal catastrophes that are char- (Fig. 1B). This process of target-primed and audio files of most presentations are available on the acteristic of cancer, neurological disorders, reverse transcription (TPRT) (4) is also NAS Web site at www.nasonline.org/telomerase_and_re- trotransposons. and aging, as occurs when telomerase and used for cDNA synthesis at telomeres, Author contributions: M.B., M.J.C., and N.F.L. wrote the retrotransposon RTs escape normal con- where the telomerase RT (TERT) uses paper. trols. A central question in genome bi- a3′-OH that occurs naturally at chromo- The authors declare no conflict of interest. ology then is how the activity of RTs has some ends to prime TPRT. In contrast, 1 fi To whom correspondence may be addressed. E-mail: been harnessed, regulated, and modi ed LTR retrotransposons and retroviral RNA [email protected], [email protected], or nflue@ throughout evolution to generate diversity templates are first reverse transcribed, and med.cornell.edu. 20304–20310 | PNAS | December 20, 2011 | vol. 108 | no. 51 www.pnas.org/cgi/doi/10.1073/pnas.1100269109 Downloaded by guest on September 27, 2021 SACKLER SPECIAL FEATURE: INTRODUCTION Arabidopsis thaliana, one of the two TERs acts as a repressor rather than a stimulator of telomere elongation, possibly by form- ing an inactive complex with the catalytic TERT (15). This finding illustrates the adaptability of telomerase components. The versatility of the telomerase ribo- nucleoprotein (RNP) is further reflected in the diversity of DNA sequences that it synthesizes. Neal Lue highlighted the ex- traordinary variability of the telomere re- peat units in a group of budding yeasts that include both Saccharomyces and Candida species. Whereas the repeat units are 5–8 bp and G-rich in most phyla, the ones in budding yeast can be as long as 25 bp and exhibit little nucleotide bias on either strand (16). The selection pressures that resulted in telomere sequence divergence in these and other organisms are not understood and are worthy of further analyses. Another example of the plasticity of retroelements is the group II intron, which is thought to be of bacterial origin and is widely hypothesized to be ancestral to the prevalent eukaryotic spliceosomal introns. Group II intron RNAs are unusual retro- elements in that they are ribozymes that encode RT. After self-splicing, the intron can reverse-splice into a DNA target and be reverse transcribed by TPRT, similar to TP-retrotransposition and telomere syn- ′– ′ Fig. 1. Featured retroelements. (A) Architecture of retroelements. RNA maps (5 3 , green) show RT thesis (3, 17). Marlene Belfort’s lecture (red). The schematic is not to scale. Stem-loops flanking the group II intron RT represent catalytic RNA, and the wavy line represents the RNA component of telomerase (TER). The hatches indicate that TERT addressed the paradox that arises from the and TER are encoded by separated genes. Boxed triangles designate LTRs. Coding sequences are GAG, compelling hypothesis that group II in- Gag protein; PR, protease; IN, integrase; ENV, envelop protein; EN, endonuclease; TEN, telomerase es- trons, found exclusively in prokaryotes and sential N terminus; and TRBD, telomerase RNA-binding domain. (B) Initiation of cDNA synthesis by RT. eukaryotic organelles, are the progenitors RTs are shown at telomere and within chromosome. TERT acts on 3′-OH at a telomere, whereas the RT of of spliceosomal introns, which are unique EN-proficient TP retrotransposons acts on the 3′-OH at a double-strand break. The green wavy line in- to and abundant in eukaryotic nuclei. To dicates