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Both Sense and Antisense Strands of the LTR of the Schistosoma Mansoni Pao-Like Retrotransposon Sinbad Drive Luciferase Expression

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Both Sense and Antisense Strands of the LTR of the Schistosoma Mansoni Pao-Like Retrotransposon Sinbad Drive Luciferase Expression Mol Genet Genomics DOI 10.1007/s00438-006-0181-1 ORIGINAL PAPER Both sense and antisense strands of the LTR of the Schistosoma mansoni Pao-like retrotransposon Sinbad drive luciferase expression Claudia S. Copeland · Victoria H. Mann · Paul J. Brindley Received: 20 August 2006 / Accepted: 4 October 2006 © Springer-Verlag 2006 Abstract Long terminal repeat (LTR) retrotranspo- activity in HeLa cells. The ability of the Sinbad LTR to sons, mobile genetic elements comprising substantial transcribe in both its forward and inverted orientation proportions of many eukaryotic genomes, are so represents one of few documented examples of bidirec- named for the presence of LTRs, direct repeats about tional promotor function. 250–600 bp in length Xanking the open reading frames that encode the retrotransposon enzymes and struc- Keywords Schistosome · Boudicca · Promotor · tural proteins. LTRs include promotor functions as Promoter · Bidirectional · Inverse well as other roles in retrotransposition. LTR retro- transposons, including the Gypsy-like Boudicca and the Pao/BEL-like Sinbad elements, comprise a sub- Introduction stantial proportion of the genome of the human blood Xuke, Schistosoma mansoni. In order to deduce the Eukaryotic genomes generally contain substantial capability of speciWc copies of Boudicca and Sinbad amounts of repetitive sequences, many of which repre- LTRs to function as promotors, these LTRs were sent mobile genetic elements (e.g., Lander et al. 2001; investigated analytically and experimentally. Sequence Holt et al. 2002). These mobile elements have played analysis revealed the presence of TATA boxes, canoni- fundamental roles in host genome evolution (Charles- cal polyadenylation signals, and direct inverted repeats worth et al. 1994; Deininger and Batzer 2002). within the LTRs of both the Boudicca and Sinbad ret- Although less is known about the genome of the platy- rotransposons. Inserted in the reporter plasmid pGL3, helminth parasite Schistosoma than more extensively the LTR of Sinbad drove WreXy luciferase activity in studied genomes such as human and mouse, recent HeLa cells in its forward and inverted orientation. In Wndings suggest that up to half of this genome may be contrast, the LTR of Boudicca did not drive luciferase comprised of repetitive sequences, and much of this repetitive complement will consist of mobile genetic elements (see Brindley 2005). Within this population Communicated by M.-A. Grandbastien. of mobile elements, 15% or more of the schistosome genome may be composed of long terminal repeat C. S. Copeland · V. H. Mann · P. J. Brindley (LTR) retrotransposons (Copeland et al. 2005b). Department of Tropical Medicine, and Interdisciplinary Long terminal repeat retrotransposons (and retrovi- Program in Molecular and Cellular Biology, ruses) are mobile genetic elements that reproduce Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA through an RNA intermediate. Typically 5–10 kb in length, their general structure consists of two open C. S. Copeland (&) reading frames (ORFs) Xanked by long direct terminal Center for Medical, Agricultural, and Veterinary repeats of »200–600 bp in length. These LTRs play a Entomology, USDA Agricultural Research Service, 1700 SW 23rd Drive, Gainesville, FL 32608, USA pivotal role in retrotransposition and transcription ini- e-mail: [email protected] tiation. The 5Ј LTR encodes the promotor, which 13 Mol Genet Genomics directs transcription by host cell RNA polymerase II. Retrotransposon LTRs and associated regulatory ele- The LTRs’ roles in retrotransposition include the nine- ments can be considered just as critical as the coding step process of reverse transcription (Gilboa et al. sequences in that they can facilitate transposition of 1979) and the integration of the proviral form of the the retroelement, even when the coding sequence is retrotransposon or retrovirus into the host cell chro- too degraded to encode functional proteins. Transposi- mosomes (Sharon et al. 1994; Hindmarsh and Leis tion of degenerate retrotransposons incapacitated by 1999). LTRs are constituted of three main parts, the internal mutation(s) can be accomplished through the U3 unique region, the repeated (R) region, and the U5 activity of functional proteins encoded by non-mutated unique region (CoYn et al. 1997) (Fig. 1a). The U3 copies, a process known as retrotransposition in trans region includes both promotor and enhancer elements, (Curcio and GarWnkel 1994). and is only found in the 3Ј LTR in the RNA genome of The inXuence of LTRs extends beyond transcription the retrotransposon, since transcription begins down- and transposition of the retrotransposons and retrovi- stream of the U3 in the 5Ј LTR. Transcription begins at ruses themselves. They have also been co-opted by (and deWnes) the 5Ј end of the R region, which is their host genomes as promotors of native genes (Med- repeated at both ends of the transcript. The U5 from strand et al. 2001; Dunn et al. 2003). In some of these the 3Ј LTR is replaced with a poly-A tail, so that in the cases, the LTRs serve as alternative promotors that are transcript, the U5 is only found in the 5Ј LTR (CoYn utilized in addition to the native promotors, and some et al. 1997). The U5 region includes a GT-rich region of these initiate transcription in a tissue speciWc man- that encodes control elements for 3Ј end processing. ner. For example, the human endothelin B receptor The R region is integral to the transfer of DNA synthe- utilizes an LTR derived promotor in addition to its sis between the 5Ј and 3Ј ends of the mRNA template native promotor, but the LTR driven transcripts during reverse transcription. The poly-A tail begins at appear only in placental tissue (Medstrand et al. 2001). the end of the R region of the 3Ј LTR, and by doing so Since expression of LTR retrotransposons has been deWnes the 3Ј boundary of the R region. The polyaden- shown to increase in tissues related to reproduction ylation signal is located either in the 3Ј end of the U3 (Dupressoir and Heidmann 1996; Lecher et al. 1997), region or in the R region. (Polyadenylation signals this pattern of transcription by LTRs acting as promo- found outside the LTRs of retroviruses such as HTLV- tors of native genes is a logical adaptation of function 1 are associated with reverse ORFs (Cavanagh et al. by the host genome. 2006). LTR retrotransposons and simpler retroviruses Schistosomiasis is considered the most important of contain only forward ORFs.) Located at the distal mar- the human helminthiases, and ranks second only to gin of many LTR retrotransposons are small repeats of malaria among all tropical diseases, in terms of mor- sequence TCN-NCA, termed the Dinucleotide bidity and mortality (Chitsulo et al. 2004). Up to 15% Inverted Repeats (DIR) (Bowen and McDonald 1999). of the schistosome genome may be composed of LTR These repeats are the byproducts of the loss of two retrotransposons (Copeland et al. 2005b). Understand- nucleotides (nt) in the initial nucleophilic attack which ing structural and functional aspects of these elements begins the process of integration of the retrotranspo- will enhance the general understanding of the schisto- son into the genome of the host (Hindmarsh and Leis some genome. It is hoped that this will guide improve- 1999). Longer (at least »8–12 bp for retroviruses), ments in the control of schistosomiasis, including the often perfectly inverted terminal sequences (terminal development of vaccines and new antiparasite medica- inverted repeats, or TIRs) are required for recognition tions. In addition to their natural roles as the promo- by integrase during the process of integration into host tors of LTR retrotransposons, LTRs are of interest for genomic DNA (Katzman et al. 1989). their potential in applications related to transgenesis Three other key elements associated with the LTR (i.e., Tanaka et al. 1998). Because of their natural tar- are the primer binding site (PBS), polypurine tract get speciWcity, LTRs of native schistosome retrotrans- (PPT), and encapsidation sequence, psi (). The PBS, posons are of potential use as components of located immediately downstream of the 5Ј LTR, is the transgenesis vectors to facilitate integration into the binding site for the tRNA primer for negative strand schistosome genome. Transduction of Schistosoma DNA synthesis. The PPT is located at the other end of mansoni using retroviral constructs has recently been the retrotransposon, just upstream of the 3Ј LTR, and demonstrated (Kines et al. 2006). Stable integration of is involved in the second (plus strand) DNA strand transgenes into the genome would in turn enable the synthesis during reverse transcription. Downstream of investigation of schistosome gene function and the devel- the PBS and overlapping gag is the encapsidation opment of transgenic schistosomes. The promotor func- sequence (), also known as the packaging signal. tions of LTRs could also be exploited in transgenesis 13 Mol Genet Genomics Fig. 1 Generalized structure of an LTR (a) and sequence alignments of 5Ј and 3Ј LTRs of (b) Sinbad and (c) Boudic- ca. Dinucleotide inverted repeats (DIRs) are marked with solid underline (red in online version). Seven nucleo- tide terminal inverted repeats in the Sinbad LTR are identi- Wed with double underline (orange in online version). Possible transcription initia- tion sites (TATA and CAAT sequences) are indicated with round dotted underline (green in online version). Polyadeny- lation signals (AATAAA or AATATA) are marked with square dotted underline (blue in online version). A GT rich region in Sinbad’s LTR is marked with dashed under- line (purple in online version) systems if the LTRs have been demonstrated to be of Boudicca and Sinbad and their ability to drive WreXy capable of initiating transcription. luciferase expression in mammalian cells. We cloned Boudicca and Sinbad are discrete LTR retrotranspo- both forward and reverse versions of each LTR into sons recently characterized from the genome of S. the luciferase expression vector pGL3, transformed mansoni (Copeland et al.
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