The take and give between retrotransposable elements and their hosts

Abstract

Retrotransposons mobilize via RNA intermediates and usually carry with them the agent of their mobility, reverse transcriptase. Retrotransposons are streamlined, and therefore rely on host factors to proliferate. However, retrotransposons are exposed to cellular forces that block their paths. For this review, we have selected for our focus elements from among target-primed (TP) retrotransposons, also called non-LTR retrotransposons, and extrachromosomally-primed (EP) retrotransposons, also called LTR retrotransposons. The TP retrotransposons considered here are group II introns, LINEs and SINEs, whereas the EP elements considered are the Ty and Tf retrotransposons, with a brief comparison to retroviruses. Recurring themes for these elements, in hosts ranging from bacteria to humans, are tie-ins of the retrotransposons to RNA metabolism, DNA replication and repair, and cellular stress. Likewise, there are parallels among host-cell defenses to combat rampant retrotransposon spread. The interactions between the retrotransposon and the host, and their coevolution to balance the tension between retrotransposon proliferation and host survival, form the basis of this review.

Figure 1

Comparison of EP and TP retrotransposition pathways. The retrotransposon is colored red throughout; LTRs are represented by boxed, black arrowheads; gray lines represent donor chromosomes. The retrotransposon transcripts (A & B, step 1) are represented by red wavy lines, that are subsequently translated and reverse transcribed into cDNA. (A) Retrotransposition of EP retrotransposons. After cDNA synthesis (A, step 2) integrase or recombinase, represented by two black dots, allows target site (TS) access (A, step 3), in generating a TS duplication of uniform length (A, steps 4 and 5). (B) Retrotranspositon of TP retrotransposons. The first step of TPRT usually involves endonuclease cleavage of the first strand of the chromosomal DNA TS (B, step 2), exposing the 3′ hydroxyl that serves as the primer for reverse transcription (B, step 3). Late steps are conducted by host repair functions (B, step 4).

Figure 2

Retrotransposon architecture. RNA maps of the retrotransposons described in this review are shown, with the reverse transcriptase (RT) sequence in red (not to scale). Rectangles represent protein-coding sequences. The stem-loops flanking the group II intron ORF represent the catalytic RNA. Coding sequences are as follows: M = maturase, EN = endonuclease, GAG = gag protein , PR = protease, IN = integrase, RH = ribonuclease H domain, Pol = polymerase domain, ENV = envelope protein. UTR = untranslated region, A_(n) = poly(A) tail, L_a = left-arm region, A_r = adenosine-rich region, R_a = right-arm region, boxed triangles = LTRs. Some group II introns lact the EN domain (see text).

Figure 3

Retromobility pathways of bacterial group II introns. (A) Endonuclease-dependent pathway via dsDNA. Reaction steps are as follows: (1) reverse splicing into DNA target, (2) bottom strand cleavage by IEP endonuclease, (3 and 4) cDNA synthesis by IEP RT, represented by solid red line (5) removal of intron RNA (6) second strand cDNA synthesis, and (7) ligation. Stimulatory (green) and inhibitory (red) host functions are superimposed on the schematic, with an arrow pointing to their putative site of action (adapted from 181). (B) Endonuclease-independent pathway via ssDNA at the replication fork. Newly replicated DNA is represented by a gray line. Reaction step numbering corresponds to (A). These pathways are for retrohoming or retrotransposition in different intron/bacterial combinations as shown in the sidebar table. Global effectors that influence retromobility are listed in Table 1. [Table: see text]

Figure 4

L1 retrotransposition pathway. The L1 retrotransposon is transcribed in the nucleus from an internal Pol II promoter and the resulting full-length RNA is exported to the cytoplasm. ORF1 and ORF2 are translated and subsequently form an RNP which may form a higher order structure. The resulting RNP is transported into the nucleus where retrotransposition takes place by TPRT. Steps are as follows: (1) transcription, (2) export to cytoplasm and translation, (3) RNP formation, (4) first strand cleavage, (5) cDNA synthesis, (6) second-strand cleavage, (7) second-strand cDNA synthesis, (8) repair, (9) ligation. Host factors involved are indicated in green (stimulatory) or red (inhibitory) at their putative site of action.

Figure 5

Ty retrotransposition cycle. Wavy red lines represent retrotransposon RNA; the red rectangle is the DNA copy of the retrotransposon. Blue dots represent the Gag structural protein; blue and green shapes represent the Gag-Pol polyprotein. Hexagons represent the virus-like particle (VLP). The stages in the pathway are as follows: (1) transcription of Ty element by RNA polymerase II, (2) transport into the cytoplasm (3) translation of retrotransposon mRNA, (4) VLP assembly and retrotransposon mRNA packaging, (5) reverse transcription, (6) import into the nucleus, and (7) integration of cDNA into the genome. Stimulatory (green) and inhibitory (red) host functions are represented near their putative sites of action. An enlargement of stages 3 and 4 is provided to illustrate the localization of Ty RNA and proteins in mRNA processing bodies (P body, grey enclosure). An active translation complex is indicated by binding of the GpppX cap of the mRNA to translation initiation factors (eIFs) and binding of the poly(A) tail to poly(A) binding protein, Pab1. Shortening of the poly(A) tail (deadenylation, dotted arrows) is the major mechanism of disassociation of mRNA from the translation initiation complex and binding by the decapping co-activators, Pat1, Dhh1 and Lsm1−7 (chain of grey ovals). These factors promote the localization of mRNA in P bodies, where mRNA decapping by Dcp1/Dcp2 and 5′−3′ degradation by Xrn1 occurs. VLP assembly may occur in P bodies.