The diversity of retrotransposons and the properties of their reverse transcriptases

Abstract

A number of abundant mobile genetic elements called retrotransposons reverse transcribe RNA to generate DNA for insertion into eukaryotic genomes. Four major classes of retrotransposons are described here. First, the long-terminal-repeat (LTR) retrotransposons have similar structures and mechanisms to those of the vertebrate retroviruses. Genes that may enable these retrotransposons to leave a cell have been acquired by these elements in a number of animal and plant lineages. Second, the tyrosine recombinase retrotransposons are similar to the LTR retrotransposons except that they have substituted a recombinase for the integrase and recombine into the host chromosomes. Third, the non-LTR retrotransposons use a cleaved chromosomal target site generated by an encoded endonuclease to prime reverse transcription. Finally, the Penelope-like retrotransposons are not well understood but appear to also use cleaved DNA or the ends of chromosomes as primer for reverse transcription. Described in the second part of this review are the enzymatic properties of the reverse transcriptases (RTs) encoded by retrotransposons. The RTs of the LTR retrotransposons are highly divergent in sequence but have similar enzymatic activities to those of retroviruses. The RTs of the non-LTR retrotransposons have several unique properties reflecting their adaptation to a different mechanism of retrotransposition.

Figure 1

Structure and phylogenetic relationship of the various groups of retrotransposons. Left side: phylogenetic relationship of the retrotransposons based on the sequence of their reverse transcriptase domains. The figure is not intended to represent a specific phylogenetic analysis, rather it represents a summary of the generally accepted relationships based on a number of different studies (Eickbush, 1994; Goodwin and Poulter, 2004; Arkhipova et al. 2003) and rooted on the sequences of telomerase and bacterial reverse transcriptases. All elements within a specific lineage are represented by a box labeled with the commonly used name to describe the elements. Above the three lineages of LTR-retrotransposons are names suggested by the International Committee on the Taxonomy of Viruses to indicate some members of the lineage may be viruses (Boeke et al., 2005; Eickbush et al., 2005). Right side: common structures for the elements in each group. If significant structural variation occurs within a group, then two structures are diagrammed to represent the types of variation most commonly seen. The open reading frames (ORFs) of each element are shown as horizontal boxes. Multiple ORFs in the same element may be in different reading frames or separated by termination codons. ORFs with similarity to the gag, pol and env genes of vertebrate retroviruses are labeled as such. Abbreviations for protein encoding domains: RT, reverse transcriptase DNA polymerase domain; RH, reverse transcriptase RNase H domain; PR, proteinase, IN; integrase; T, tether; APE, apurinic endonuclease; EN, endonuclease; Uri, domain similar to the endonuclease of some mobile group I introns; YR, domain with similarity to tyrosine recombinanses. Shaded arrowheads in boxes, long terminal repeats (LTRs) or internal complimentary repeats (ICR) with sequence identity to the LTRs; thin lines, non-translated regions of the elements; AAA, poly(A) tails.

Figure 2

Model for non-LTR retrotransposition based solely on studies of the R2 element. The single ORF of R2 is translated into one protein which contains both RT and endonuclease domains (see Figure 1, top non-LTR retrotransposon structure). R2 protein subunits bind either the 3′ or 5′ end of the R2 transcript to make the RNP complex used for retrotransposition. The RNA end bound determines whether the subunit binds upstream or downstream of the insertion site on the target DNA. The protein subunit bound upstream of the insertion site cleaves the lower DNA strand and use the released 3′ end to prime reverse transcription of the RNA (steps 1 and 2). The protein subunit bound downstream of the insertion site cleaves the upper DNA strand and uses the released 3′ end to prime second-strand DNA synthesis. RNA still bound to the first DNA strand is displaced during this synthesis. For further details of the model see Luan et al., 1993; Christensen et al., 2006; Kurzynska-Kokorniak et al., 2007. While the precise details of protein binding to the RNA transcript and the DNA target site may only be relevant for the R2 elements, the general steps of the reaction, including the use of the first and second strand cleavages to prime the two DNA strands is likely to be common for many non-LTR elements (see review by Ostertag and Kazazian, 2001).