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• W2187579891 abstract "In this issue, Ahl et al., 2015Ahl V. Keller H. Schmidt S. Weichenrieder O. Mol. Cell. 2015; 60 (this issue): 715-727Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar and Doucet et al., 2015Doucet A.J. Wilusz J.E. Miyoshi T. Liu Y. Moran J.V. Mol. Cell. 2015; 60 (this issue): 728-741Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar illuminate structural and functional features of substrates that promote integration of RNA molecules into the human genome by LINE retrotransposons, contributing to the ∼50% of the human genome that has been colonized by mobile genetic elements. In this issue, Ahl et al., 2015Ahl V. Keller H. Schmidt S. Weichenrieder O. Mol. Cell. 2015; 60 (this issue): 715-727Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar and Doucet et al., 2015Doucet A.J. Wilusz J.E. Miyoshi T. Liu Y. Moran J.V. Mol. Cell. 2015; 60 (this issue): 728-741Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar illuminate structural and functional features of substrates that promote integration of RNA molecules into the human genome by LINE retrotransposons, contributing to the ∼50% of the human genome that has been colonized by mobile genetic elements. Over half of the human genome is made up of mobile or repetitive genetic elements such as retrotransposons and endogenous retroviruses. How do retrotransposons preferentially integrate their own RNA as opposed to other cellular RNAs? Some retrotransposons are non-autonomous and cannot replicate without co-opting proteins from autonomous systems; how do they accomplish this feat? In this issue, Ahl et al., 2015Ahl V. Keller H. Schmidt S. Weichenrieder O. Mol. Cell. 2015; 60 (this issue): 715-727Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar and Doucet et al., 2015Doucet A.J. Wilusz J.E. Miyoshi T. Liu Y. Moran J.V. Mol. Cell. 2015; 60 (this issue): 728-741Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar illuminate a complex network of interactions between retrotransposon ribonucleoproteins (RNPs), poly-A tails, and the translating ribosome that proves a nearly 20-year-old model (Boeke, 1997Boeke J.D. Nat. Genet. 1997; 16: 6-7Crossref PubMed Scopus (203) Google Scholar), while raising exciting questions for the future. The majority of the retrotransposon-colonized human genome is derived from either long interspersed element-1 (LINE-1; ∼17%) or short interspersed element (SINE; ∼11%) sequences (Richardson et al., 2015Richardson S.R. Doucet A.J. Kopera H.C. Moldovan J.B. Garcia-Perez J.L. Moran J.V. Microbiol. Spectr. 2015; 3 (MDNA3–0061–2014)Crossref Scopus (167) Google Scholar). LINE-1 elements encode two open reading frames dubbed ORF1 and ORF2, while SINE elements, including the Alu family, do not encode proteins. ORF1p is an RNA-binding protein of mysterious function that coats LINE-1 RNA and traffics the LINE-1 RNP to RNA granules. ORF2p is a reverse transcriptase and endonuclease that mediates retrotransposition of LINE-1 elements. On the other hand, Alu elements are non-autonomous and must utilize LINE-1 ORF2p for retrotransposition. Both LINE-1 and Alu elements contain stretches of adenosine, but the role of the poly-A region and the mechanism by which Alu RNPs hijack ORF2p for reverse transcription has remained mysterious. Alu elements are derived from the 7SL noncoding RNA, which forms the RNA core of the signal recognition particle (SRP). The SRP detects the presence of nascent transmembrane (TM) signal peptides and stalls the ribosome prior to engagement with the translocon (Wolin and Walter, 1989Wolin S.L. Walter P. J. Cell Biol. 1989; 109: 2617-2622Crossref PubMed Scopus (98) Google Scholar). Recent structural work showed that the SRP stably interacts with translating ribosomes in multiple states of elongation while sampling the nascent chain to detect TM sequences (Voorhees and Hegde, 2015Voorhees R.M. Hegde R.S. eLife. 2015; 4: e07975Crossref Scopus (86) Google Scholar). Now, Weichenrieder and colleagues show that the Alu RNP (containing half of the Alu RNA and SRP9/14 heterodimer) is structurally similar to the SRP, and that the most conserved region of the Alu RNA interacts with a highly conserved region of the ribosome (Ahl et al., 2015Ahl V. Keller H. Schmidt S. Weichenrieder O. Mol. Cell. 2015; 60 (this issue): 715-727Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). This observation motivates the provocative suggestion that Alu elements may predate elongation factors as part of primordial translation systems. Both Alu and LINE-1 elements contain poly-A stretches that are genomically encoded or co-transcriptionally added, respectively. This “poly-A connection” was hypothesized to be the basis for both the preferential cis-preference of LINE-1 (that is, the mRNA producing nascent LINE-1 ORF2p is preferentially targeted) and hijacking of LINE-1 ORF2p by Alu elements in trans (Boeke, 1997Boeke J.D. Nat. Genet. 1997; 16: 6-7Crossref PubMed Scopus (203) Google Scholar). In support, poly-A binding protein (PABP) is essential for LINE-1 retrotransposition (Dai et al., 2012Dai L. Taylor M.S. O’Donnell K.A. Boeke J.D. Mol. Cell. Biol. 2012; 32: 4323-4336Crossref PubMed Google Scholar), and the length of A-tails encoded by Alu elements is positively correlated with the efficiency of retrotransposition (Dewannieux and Heidmann, 2005Dewannieux M. Heidmann T. Genomics. 2005; 86: 378-381Crossref PubMed Scopus (59) Google Scholar, Roy-Engel et al., 2002Roy-Engel A.M. Salem A.-H. Oyeniran O.O. Deininger L. Hedges D.J. Kilroy G.E. Batzer M.A. Deininger P.L. Genome Res. 2002; 12: 1333-1344Crossref PubMed Scopus (112) Google Scholar). Moran and colleagues now show that ORF2p preferentially associates with LINE-1 messages with a poly-A tail and that the efficiency of trans-mobilization of Alu elements increases when LINE-1 is not A-tailed (Doucet et al., 2015Doucet A.J. Wilusz J.E. Miyoshi T. Liu Y. Moran J.V. Mol. Cell. 2015; 60 (this issue): 728-741Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). The structure of the Alu RNP advances the “cis-preference by elongation arrest” model, where the Alu RNP increases the duration of ribosome stalls to increase the likelihood that its A-tail can outcompete the LINE-1 message for ORF2p (Ahl et al., 2015Ahl V. Keller H. Schmidt S. Weichenrieder O. Mol. Cell. 2015; 60 (this issue): 715-727Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). This model raises a number of questions. The SRP slows ribosome translocation (Wolin and Walter, 1989Wolin S.L. Walter P. J. Cell Biol. 1989; 109: 2617-2622Crossref PubMed Scopus (98) Google Scholar). Do Alu RNPs also slow translocation? If so, does this occur on cellular messages as well (Figure 1A)? What fraction of the transcriptome might be influenced by this behavior, and is it context dependent? ORF2p is a large, ∼150 kDa protein; do multiple ribosomes load on a single ORF2 reading frame? If so, Alu would win by default on all but the first ORF2p produced as there will be no LINE-1 message to compete with it, perhaps partially explaining its success in colonizing the human genome with over 106 copies (Richardson et al., 2015Richardson S.R. Doucet A.J. Kopera H.C. Moldovan J.B. Garcia-Perez J.L. Moran J.V. Microbiol. Spectr. 2015; 3 (MDNA3–0061–2014)Crossref Scopus (167) Google Scholar). These studies make a number of important predictions in health and disease. Confirmation of the poly-A connection puts forward a model where kinetic competition for nascent ORF2p proteins by the menagerie of cellular adenylated RNAs determines which RNA is retrotransposed into the host genome (Figure 1B). As translation elongation is slowed in numerous circumstances such as mitosis (Sivan et al., 2011Sivan G. Aviner R. Elroy-Stein O. J. Biol. Chem. 2011; 286: 27927-27935Crossref PubMed Scopus (37) Google Scholar), processed pseudogene formation might increase when cells are cycling more rapidly. Indeed, in certain cancers, which are typified by uncontrolled cell division, novel somatic pseudogenes have been discovered that sometimes affect tumor suppressors (Cooke et al., 2014Cooke S.L. Shlien A. Marshall J. Pipinikas C.P. Martincorena I. Tubio J.M.C. Li Y. Menzies A. Mudie L. Ramakrishna M. et al.ICGC Breast Cancer GroupNat. Commun. 2014; 5: 3644Crossref PubMed Scopus (70) Google Scholar). These observations suggest that an increase in pseudogene formation should be investigated in other circumstances where global translation elongation is altered. The role of polyadenosine stretches in recruiting the to-be-transposed message to ORF2p is clear, but a number of important questions persist regarding how this occurs in the context of active translation (Figure 1B). For example, since PABP is required for LINE-1 retrotransposition (Dai et al., 2012Dai L. Taylor M.S. O’Donnell K.A. Boeke J.D. Mol. Cell. Biol. 2012; 32: 4323-4336Crossref PubMed Google Scholar), what are the direct interactions between ORF2p and mRNA? Does PABP bound to the Alu RNP compete for the mRNA cap-binding complex as proposed (Dewannieux and Heidmann, 2005Dewannieux M. Heidmann T. Genomics. 2005; 86: 378-381Crossref PubMed Scopus (59) Google Scholar and Roy-Engel et al., 2002Roy-Engel A.M. Salem A.-H. Oyeniran O.O. Deininger L. Hedges D.J. Kilroy G.E. Batzer M.A. Deininger P.L. Genome Res. 2002; 12: 1333-1344Crossref PubMed Scopus (112) Google Scholar), or does ORF2p displace PABP and directly bind to the poly-A region? How is this complex disassembled and shuttled to the nucleus? Is there a role for ORF1p in these processes? With exciting results and new directions for the future, our understanding of retrotransposons is likely to remain mobile. Retrotransposition and Crystal Structure of an Alu RNP in the Ribosome-Stalling ConformationAhl et al.Molecular CellNovember 12, 2015In BriefAhl et al. determined the crystal structure of a conformationally closed Alu ribonucleoprotein particle that matters for the signal recognition particle and the retrotransposition of the human Alu element. A single Alu folding unit is sufficient for retrotransposition activity. It likely targets stalling ribosomes to recruit nascent L1 reverse transcriptase. Full-Text PDF Open ArchiveA 3′ Poly(A) Tract Is Required for LINE-1 RetrotranspositionDoucet et al.Molecular CellNovember 12, 2015In BriefDoucet et al. demonstrate that a 3′ poly(A) tract is required for human LINE-1-mediated retrotransposition. The ORF2p LINE-1-encoded protein preferentially associates with 3′ poly(A) tracts in LINE-1 and Alu RNAs, which helps explain their abundance in the human genome. Full-Text PDF Open Archive" @default.
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• W2187579891 title "Get in LINE: Competition for Newly Minted Retrotransposon Proteins at the Ribosome" @default.
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