Chapter 49 : Integration, Regulation, and Long-Term Stability of R2 Retrotransposons

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R2 elements exclusively insert into 28S rRNA genes ( Figure 1 ). As a result of this specificity, R2 is one of the more tractable mobile elements to study and, thus, is now among the best understood elements both in terms of its mechanism and its population dynamics. The R2 element was first identified in the rDNA loci of in the early 1980’s ( ), when little was known of the structure or abundance of mobile elements in eukaryotes. In fact, the exclusive residence of the element at a specific site in the 28S gene initially suggested that it might be an intron. However, the findings that only a fraction of the genes contained the insertion, that 28S genes containing the insertion did not appear to be transcribed, and that many of the insertions had a sizeable deletion at the 5′ end all argued against its role as an intron. Insertions were soon identified at the same position of the 28S rRNA gene in many other species of insects ( ). The complete sequence of the insertions in both and revealed a large open reading frame (ORF) encoding a reverse transcriptase that had greatest sequence similarity to that of non-LTR retrotransposons ( ). R2 differed from most non-LTR retrotransposons, however, in that it only contained a single ORF. Furthermore, rather than an encoded apurinic endonuclease (APE) located amino-terminal to the reverse transcriptase ( ), R2 encoded carboxyl terminal to the reverse transcriptase an endonuclease with an active site more similar to that of certain restriction enzymes ( ).

Citation: Eickbush T, Eickbush D. 2015. Integration, Regulation, and Long-Term Stability of R2 Retrotransposons, p 1127-1146. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0011-2014
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Figure 1

R2 elements insert within the 28S rRNA genes. The nucleolus, the site of rRNA transcription and processing, is organized around the hundreds of tandem units (rDNA units) that comprise the rDNA locus. Each rDNA unit is composed of a single transcription unit containing the 18S, 5.8S, and 28S genes (black boxes) and external and internal transcribed spacers (white boxes). The transcription units are separated by intergenic spacers (thin lines). A subset of the 28S genes in many animals contain R2 insertions near the middle of the gene (red box). R2 elements encode a single open reading frame (ORF).

Citation: Eickbush T, Eickbush D. 2015. Integration, Regulation, and Long-Term Stability of R2 Retrotransposons, p 1127-1146. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0011-2014
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Figure 2

Domain structure of the R2 protein and its similarity to other elements. At the bottom is the R2 element from with the 5′ and 3′ untranslated regions indicated by dotted lines. The central region of the encoded protein contains the reverse transcriptase domain. The various conserved motifs within the fingers and palm regions (motifs 1–7) and the predicted thumb are indicated. An RNA binding domain is immediately N-terminal to the reverse transcriptase and conserved motifs within this domain are labeled 0 and −1. The N-terminal region of the protein contains zinc finger (Zn) and c-myb (Myb) motifs, while the C-terminal region encodes a putative zinc-binding domain and the R2 endonuclease. Shown below the R2 diagram are the 5′ and 3′ regions of the R2 RNA that are bound by the R2 protein during a retrotransposition reaction (see Figure 4 ). The major difference among R2 elements from different species is the presence of one, two, or three zinc finger domains at the N-terminal end. The R2 element from horseshoe crab is an example of the latter. Comparison of the R2 protein with the gene of LTR retrotransposons (and retroviruses) reveals little in common except for 7 out of the 9 motifs in the reverse transcriptase domain. Most LTR retrotransposon genes also encode an RNase H and integrase not found in R2. The R2 protein has greater similarity to the proteins encoded by group II introns and telomerases. These three groups share all nine motifs of the reverse transcriptase. In the case of telomerase, these motifs are frequently termed 1, 2, 3, A, IFD, B, C, D, and E (from left to right) ( ). Group II introns, telomerases, and R2 also share an RNA binding domain upstream of the reverse transcriptase (purple segment). Group II introns and R2 both encode an endonuclease domain at the 3′ end, while R2 and some telomerases have DNA binding domains (TEN) at the N-terminal end.

Citation: Eickbush T, Eickbush D. 2015. Integration, Regulation, and Long-Term Stability of R2 Retrotransposons, p 1127-1146. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0011-2014
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Figure 3

The R2 ribozyme. (A) An rDNA transcription unit is diagramed with 18S, 5.8S, and 28.S genes (gray boxes), transcribed spacers (white boxes), and R2 insertion (black box). All three rRNAs are normally processed from the single primary transcript. When a unit contains an R2 insertion, a self-cleaving ribozyme encoded at the 5′ end of the element releases the 5′ end of the R2 transcript from the upstream 28S rRNA sequence. It is not known if transcription ends at the 3′ end of the R2 element, or if this end is processed from downstream 28S gene sequences. (B) On the left is the R2 ribozyme folded in a structure similar to that of the hepatitis delta virus (HDV) ribozyme ( ). The various components of the ribozyme are labeled as in the HDV ribozyme: P, base-paired region; L, loop; J, nucleotides joining paired regions. 28S gene sequences are shaded with gray. On the right is the R2 ribozyme from (earwig). Self-cleavage (arrow) occurs at the precise junction of the R2 element with the 28S gene in the case of the element and upstream of the junction in the 28S gene sequences in the case of the R2 element from .

Citation: Eickbush T, Eickbush D. 2015. Integration, Regulation, and Long-Term Stability of R2 Retrotransposons, p 1127-1146. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0011-2014
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Figure 4

The R2 retrotransposition model. An R2 integration reaction is proposed to involve symmetric cleavage/DNA synthesis steps by R2 proteins bound upstream and downstream of the insertion site. From top to bottom, protein bound upstream of the insertion site is associated with the 3′ end of the R2 transcript. This protein both cleaves the bottom stand of DNA and catalyzes the reverse transcription of the R2 RNA using the cleaved DNA target as primer, target primed reverse transcription (TPRT). R2 protein bound downstream of the insertion site is associated with the 5′ end of the R2 transcript. When the reverse transcription reaction catalyzed by the upstream protein dislodges the 5′ RNA, the downstream protein cleaves the top DNA strand and again uses the cleaved DNA to prime second strand DNA synthesis. Second strand synthesis requires the polymerase to displace the R2 RNA. Because in the absence of bound RNA the downstream protein does not bind tightly to the DNA target, it is shown dissociated from the target site during polymerization. The integration reaction is completed by the host repair machinery which fills in the single stranded gaps at the target site. Blue oval, protein subunit (dark, active; light, inactive); wavy black line, R2 RNA; dashed red lines, synthesized DNA; solid black lines; target DNA.

Citation: Eickbush T, Eickbush D. 2015. Integration, Regulation, and Long-Term Stability of R2 Retrotransposons, p 1127-1146. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0011-2014
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Figure 5

Variation in the priming of second-strand DNA synthesis. R2 elements differ in whether the 5′ end of the RNA template used in the integration reaction ends at the boundary between R2 and the 28S gene or extends a short distance upstream in the 28S rRNA sequence. This difference is dependent upon the location of the self-cleavage site by the R2 ribozyme (see text). Left panel. If self-cleavage by the R2 ribozyme is upstream in the 28S gene sequences, the resulting cDNA strand can form a heteroduplex with the upstream target DNA. This heteroduplex can stabilize the integration intermediate resulting in precise initiation of second strand synthesis (arrow) and uniform 5′ ends for different R2 copies. Right panel. If self-cleavage is at the 28S/R2 junction, there are no 28S sequences on the DNA strand (cDNA) generated by reverse transcription. As a consequence, the R2 protein must use regions of microhomology to initiate second strand synthesis (arrow). Priming frequently involves the 3–5 non-templated nucleotides added to the cDNA strand as the enzyme ran off the RNA template (lower case n’s). This use of chance microhomologies to prime second strand DNA synthesis gives rise to sequence variation at the 5′ junctions of different integrated copies of R2. Wavy black line, RNA with 5′ end denoted; red dashed line, first strand DNA composed of R2 sequences; gray box, first strand DNA sequences complementary to upstream DNA target sequences.

Citation: Eickbush T, Eickbush D. 2015. Integration, Regulation, and Long-Term Stability of R2 Retrotransposons, p 1127-1146. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0011-2014
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Figure 6

The transcription domain model of the rDNA locus and the long-term stability of R2 elements. (A) Uninserted (black boxes) and R2-inserted (black boxes with red insert) rDNA units are interspersed throughout the tandem array of rRNA genes. In Drosophila, a contiguous region of the rDNA locus with the lowest level of R2 insertions is selected for transcription. For simplicity this region is drawn as only seven units, but in it is believed to be about 40 units. The remainder of the locus is packaged into heterochromatin (the compacted DNA plus protein flanking the active region). If the region selected as the transcription domain is free of R2-inserted units, then there is no R2 transcription and no R2 retrotransposition. (B) The driving force in the concerted evolution of the rDNA locus is crossovers between chromosomes. Most of these crossovers occur within the transcription domain (see text). The diagramed crossover produces one chromosome with an expanded R2 free region. Because the same number of rDNA units is still activated for transcription, some of the units that were transcribed before the crossover are packaged into heterochromatin after the crossover. Asterisks marking the original boundary of the transcription domain show this shift. The other chromosome product of the recombination contains an rDNA locus with a smaller R2-free region. In this case, rDNA units originally flanking the transcription domain are now activated for transcription. These flanking units contain R2 inserted units and thus copies of the R2 element are transcribed and retrotranspositions result.

Citation: Eickbush T, Eickbush D. 2015. Integration, Regulation, and Long-Term Stability of R2 Retrotransposons, p 1127-1146. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0011-2014
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