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• W51482956 abstract "DNA rearrangements play significant roles in human biology. The mobile DNA segments called transposons are, for example, notable contributors to disease. The HIV retrovirus is a transposable element whose integration into the human genome results in the irreversible association of the virus with its host. Bacterial transposons provide additional examples, as they promote the widespread dissemination of antibiotic resistance among bacteria. Although these elements inhabit the genomes of very different host organisms, the DNA breakage and joining reactions that underlie their transposition are chemically very similar. Furthermore, the retroviral integrases and bacterial transposases responsible for movement of these elements are structurally related and are members of the retroviral integrase superfamily of transposases. Another type of DNA rearrangement provides humans and other vertebrates with immunologic protection against attacks by bacterial, viral, and parasitic invaders. This site-specific recombination reaction, known as VDJ recombination, generates diverse T-cell receptor (TCR) and immunoglobulin (Ig) molecules that are central to the recognition of a wide variety of foreign antigens. Recent studies have revealed surprising similarities in the mechanism of VDJ recombination and of transposition reactions executed by members of the retroviral integrase superfamily. In this issue of Cell, Gellert and colleagues demonstrate that the VDJ recombinase can actually function as a transposase, at least in the test tube, catalyzing the intermolecular transposition of a discrete DNA segment (11Hiom K. Melek M. Gellert M Cell. 1998; 94 (this issue,): 463-470Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). Similar findings have been reported by Schatz and colleagues (1Agrawal A. Eastman Q.M. Schatz D.G Nature. 1998; 394: 744-751Crossref PubMed Scopus (579) Google Scholar). These findings suggest the possibility that inappropriate transposition events promoted by the VDJ recombinase may underlie various aberrant chromosomal rearrangements that can result in lymphoid neoplasms. In addition to providing new insights into the mechanism of VDJ recombination, these findings support the view that the VDJ recombination system may derive from an ancient transposon. The substrates for VDJ recombination are DNA segments, termed coding elements, flanked by short sequences called recombination signal sequences (RSSs) (Figure 1A). The lymphoid-specific proteins RAG1 and RAG2 collaborate to make a double-strand break (DSB) between each RSS and its corresponding coding segment, producing two coding ends and two signal ends. Subsequent joining of the coding ends, forming a coding joint, assembles a rearranged TCR or Ig gene segment; the signal ends also join, forming a signal joint. Several features of VDJ recombination are reminiscent of transposition (Figure 1). First, both reactions involve short specific sequences at the ends of the mobile segments that are recognized and acted upon by the recombinase. Furthermore, the individual steps of VDJ recombination resemble steps in transposition of the “cut and paste” transposons. In both reactions, the recombinase introduces DSBs that separate the recognition sequences from the flanking DNA. In transposition, after excision of the transposable element the broken donor ends are typically joined by host DNA repair mechanisms (4Coen, E., Robbins, T.P., Almeida, J., Hudson, A., and Carpenter, R. (1989). In Mobile DNA. D.E. Berg and M.M. Howe, eds. (Washington DC: ASM Press), pp. 413–436.Google Scholar, 6Engels W.R. Johnson-Schlitz D.M. Eggleston W.B. Sved J Cell. 1990; 62: 515-525Abstract Full Text PDF PubMed Scopus (332) Google Scholar, 9Hagemann A.T. Craig N.L Genetics. 1993; 133: 9-16PubMed Google Scholar). Similarly, joining of the coding ends created by VDJ recombination proceeds via an end-joining reaction that requires cellular DSB repair functions (2Bogue M. Roth D.B Curr. Opin. Immunol. 1996; 8: 175-180Crossref PubMed Scopus (90) Google Scholar). A key distinction between transposition and VDJ recombination lies in the fates of the transposon ends and the signal ends. Transposon ends are joined to a target DNA molecule by the transposase: the 3′ OH ends of the element attack the target backbone and form new phosphodiester links that insert the transposon into a different site, forming a simple insertion. In contrast, signal ends are joined by a process that requires cellular DSB repair factors: the blunt signal ends are joined by ligation, forming a signal joint (2Bogue M. Roth D.B Curr. Opin. Immunol. 1996; 8: 175-180Crossref PubMed Scopus (90) Google Scholar). There are several intimate mechanistic links between VDJ recombination and transposition. First, the chemistry of DSB formation in VDJ recombination is very similar to the chemistry of transposition (14Mizuuchi K J. Biol. Chem. 1992; 267: 21273-21276Abstract Full Text PDF PubMed Google Scholar, 22van Gent D.C. Mizuuchi K. Gellert M Science. 1996; 271: 1592-1594Crossref PubMed Scopus (237) Google Scholar). The translocation of cut and paste transposons occurs via several Mg2PLUSPUSSIGN-dependent, direct transesterification steps. In the first step, DNA cleavage, H2O is used as the nucleophile to hydrolyze phosphodiester bonds at the termini of the element, exposing a critical 3′ OH at each end of the transposon. Cleavage also occurs at the 5′ ends, disconnecting the transposon from the donor DNA. In a subsequent strand transfer step, these 3′ hydroxyl groups act as nucleophiles to join the transposon ends to the target DNA, generating a simple insertion. RAG-mediated DSB formation is also initiated by a hydrolysis step that generates a nick, exposing a 3′ OH on the coding end flanking the RSS (Figure 2A, top). As in transposition, the 3′ OH exposed by hydrolysis attacks a target DNA molecule, in this case intramolecularly such that a hairpin is formed on the coding end; the signal end is blunt, with a 3′ OH (Figure 2A, bottom). Thus, similar steps of identical chemistry—direct transesterification reactions that result in hydrolysis or strand transfer, depending on the nucleophile—underlie both transposition and formation of the DSBs that initiate VDJ recombination. Recently, a further similarity between VDJ recombination and transposition has been found in the RAG-dependent formation of a particular type of VDJ recombination junction termed a hybrid joint. These junctions result from joining a signal end to a coding end, a reaction that can be catalyzed in vitro by purified RAG proteins by a mechanism that is essentially a reversal of the cleavage step (13Melek M. Gellert M. van Gent D.C Science. 1998; 80: 301-303Crossref Scopus (91) Google Scholar). In this reaction, the 3′ OH of the signal end attacks a hairpin coding end, resulting in a covalent reattachment of an RSS to a coding end (Figure 2B). Hybrid joint formation is strictly analogous to “disintegration” reactions carried out by retroviral transposases (3Chow S.A. Vincent K.A. Ellison V. Brown P.O Science. 1992; 255: 723-726Crossref PubMed Scopus (356) Google Scholar). Furthermore, the ability to form hybrid joints provided the first evidence that the RAG proteins can perform a transposase-like joining reaction, joining signal ends to coding ends by transesterification. Gellert’s group has now shown that purified RAG1 and RAG2 can promote the intermolecular transposition in vitro of a DNA segment flanked by RSSs into a nonspecific target DNA molecule (11Hiom K. Melek M. Gellert M Cell. 1998; 94 (this issue,): 463-470Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). This reaction has all the hallmarks of transposition: it requires divalent metal ions, is independent of ATP, and requires a 3′ OH at the tip of the mobile segment for joining to a target DNA (Figure 2C). RAG-mediated transposition does not show substantial target site specificity, although some preference for G-C-rich sequences can be discerned. The 3′ hydroxyls of the two signal ends can join in a concerted fashion to a single target DNA (Figure 2C), generating a simple insertion structure resembling the simple insertions generated by such cut and paste elements as Tn7 and Tn10 in bacteria, the Drosophila P element, and the widespread Tc1/mariner elements (17Saedler H. Gierl A. Transposable Elements, Curr. Topics Microbiol. Immunol., Vol. 204. Springer-Verlag, Heidelberg1996Google Scholar). Thus, the RAG proteins can function as an authentic transposase, joining signal ends to unrelated target DNA molecules. The remarkable similarities in the reactions catalyzed by the RAG recombinase and transposases raise the question: are the RAG proteins related to transposases? No informative sequence similarities between the RAG proteins and the members of the retroviral integrase family have been identified. However, although little primary sequence homology exists between the MuA transposase and HIV integrase, analysis of the crystal structures reveals that the catalytic regions of these two proteins are remarkably similar (5Craig N.L Science. 1995; 270: 253-254Crossref PubMed Scopus (141) Google Scholar; 8Grindley N.D.F. Leschziner A.E Cell. 1995; 83: 1063-1066Abstract Full Text PDF PubMed Scopus (64) Google Scholar). The question of whether the RAG nuclease/transposase shares structural features with other transposases awaits comparative analysis of the crystal structures. It is of considerable interest to identify the roles that the RAG1 and RAG2 proteins each play in recombination. In most transposition systems, the transposase is an oligomer of a single gene product. However, in Tn7 transposition, as in VDJ recombination, two proteins collaborate and act interdependently to promote recombination (18Sarnovsky R.J. May E.W. Craig N.L EMBO J. 1996; 15: 6348-6361Crossref PubMed Scopus (109) Google Scholar). It will be interesting to compare the RAG and Tn7 transposases and the functions of their individual polypeptides in detail. The VDJ recombination system has two hallmarks of transposable elements: a recombinase and a mobile DNA segment bracketed by recombinase-binding sites. Moreover, the two RAG genes are tightly linked, lying only a few kilobases apart. These observations, along with the rapid appearance of rearranging gene segments in the immune system over a short period of evolutionary time have raised the question as to whether the VDJ system arose by the acquisition of an ancient mobile element by a distant common vertebrate ancestor (for example, see 20Thompson C.B Immunity. 1995; 3: 531-539Abstract Full Text PDF PubMed Scopus (196) Google Scholar). Further transposition events in the germline could also have contributed to the generation of the complex array of Ig and TCR gene loci (11Hiom K. Melek M. Gellert M Cell. 1998; 94 (this issue,): 463-470Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). The newly discovered ability of the RAG proteins to join signal ends to target DNA by transposition in the test tube raises a key question: does this activity play a role in the VDJ joining reactions that occur in living cells? Formation of both signal and coding joints is substantially impaired by mutations in components of the cellular DSB repair machinery, indicating that both of these joining reactions occur by ligation mechanisms rather than by transposition. Further evidence that signal joints are not formed by transposition is provided by their structure. Signal joints are characteristically precise; loss of nucleotides is almost never observed in cells proficient for double-strand break repair. Such simple end-to-end joining is not observed with transposable elements because transesterification cannot join ends without attacking a phosphodiester bond. Thus, joining of an end by transposition to a site inside the element would result in the loss of element sequences, as is observed (see for example 7Gorbunova V. Levy A.A Genetics. 1997; 145: 1161-1169PubMed Google Scholar). These observations argue that transposition activity of the RAG proteins does not play a significant role in the standard VDJ joining reactions. Under certain conditions, however, RAG-mediated transesterification may function in VDJ joining. Hybrid joints provide the clearest example. These junctions are found in wild-type cells and, with comparable frequency, in cells defective for double-strand break repair, suggesting that they are not formed by ligation (10Han J.-O. Steen S.B. Roth D.B Mol. Cell. Biol. 1997; 17: 2226-2234Crossref PubMed Scopus (57) Google Scholar). As discussed above, hybrid joints can be formed in vitro by transesterification. Thus, this reaction, which can be loosely considered a form of transposition (to a very specific target, the hairpin coding end), may be a normal feature of VDJ recombination in vivo. Malignancies arising from B- and T-cell precursors are commonly associated with chromosome translocations involving Ig and TCR loci, many of which are thought to arise from aberrant VDJ recombination events (12Korsmeyer S.J Annu. Rev. Genet. 1992; 10: 785-807Google Scholar; 21Tycko B. Sklar J Cancer Cells. 1990; 2: 1-8PubMed Google Scholar). Several mechanisms have been proposed to explain these events (discussed in 11Hiom K. Melek M. Gellert M Cell. 1998; 94 (this issue,): 463-470Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). One model suggests that the recombination machinery recognizes an authentic RSS at an Ig or TCR locus and mistakenly uses a cryptic RSS on the partner chromosome to perform VDJ recombination. In some cases, sequences resembling an RSS can be identified at the breakpoint on the partner chromosome, providing support for this model. However, there are examples where convincing RSS-like sequences cannot be identified at the breakpoint on the partner chromosome. Such translocations, which appear to involve only a single RSS, could arise from single-ended RAG-mediated transposition events (11Hiom K. Melek M. Gellert M Cell. 1998; 94 (this issue,): 463-470Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). As shown in Figure 3, attack of a signal end on the partner chromosome forms a branched structure containing a 3′ hydroxyl at the branch point. Hiom et al. have proposed that the RAG proteins use this 3′ OH as a nucleophile to attack the bottom strand, breaking the chromosome and liberating a hairpin end. Repair of the nick and joining of the two hairpin ends would complete the translocation. Although this mechanism requires a single cleavage, single site cleavage has been observed in vivo (15Nakajima P.B. Bosma M.J Mol. Cell. Biol. 1997; 17: 2631-2641PubMed Google Scholar; 19Steen S.B. Gomelsky L. Speidel S.L. Roth D.B EMBO J. 1997; 16: 2656-2664Crossref PubMed Scopus (51) Google Scholar). RAG-mediated transposition events involving two ended insertions could also give rise to translocations. As shown in Figure 4, coupled cleavage followed by transposition to form a simple insertion would generate an intermediate with 3′ hydroxyls at each end of the insert. These could be used as nucleophiles by the RAG proteins for cleavage, liberating the insert and producing a chromosome break. The hairpin chromosome ends would then be available for joining to the coding ends generated by the initial VDJ cleavage event, generating a pair of reciprocal product chromosomes that lack RSS elements (11Hiom K. Melek M. Gellert M Cell. 1998; 94 (this issue,): 463-470Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). Note that unless the signal ends are joined, the excised linear fragment might be available for further transposition events and could potentially act in a catalytic fashion to promote additional chromosome rearrangements. One intriguing feature of this model is that while the chromosomal rearrangements are catalyzed by the VDJ recombination system, no telltale RSS elements are left behind at the breakpoints. Rearrangements of this type have been observed (discussed in 11Hiom K. Melek M. Gellert M Cell. 1998; 94 (this issue,): 463-470Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). Thus, RAG-promoted chromosome translocations might be much more common than has been thought. The preceding discussion emphasizes that signal ends are potentially dangerous reaction intermediates. Thus, formation of signal joints may serve a protective function, preventing these ends from participating in transpositional rearrangements. However, signal ends have rather long half-lives in vivo (16Ramsden D.A. Gellert M Genes Dev. 1995; 9: 2409-2420Crossref PubMed Scopus (141) Google Scholar), and there could be opportunities for these ends to engage in transposition. It is important to determine how frequently such events occur in vivo. It will be interesting to see whether safeguards have evolved to keep the RAG recombinase, a transposase harnessed to perform the useful task of providing vertebrates with a powerful immunologic arsenal, from promoting dangerous liaisons." @default.
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