Discovery of an Active RAG Transposon Illuminates the Origins of V(D)J Recombination

Huang, Shengfeng; Tao, Xin; Yuan, Shaochun; Zhang, Yuhang; Li, Peiyi; Beilinson, Helen A.; Zhang, Ya; Yu, Wei; Pontarotti, Pierre; Escrivà, Héctor; Pétillon, Yann Le; Liu, Xiaolong; Chen, Shangwu; Schatz, David G.; Xu, Anlong

doi:10.1016/j.cell.2016.05.032

Cited by 170 publications

(211 citation statements)

References 46 publications

(66 reference statements)

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“…4G, 6–7), and the proper communication between RNH domains depends on the NBD domains binding to nonamers. Acquisition of the NBD domain by RAG1 differentiates the chordates that carry out V(D)J recombination from those that do not (Huang et al, 2016). It may be surprising that the truncated RAG1/2 without NBD binds RSS DNAs as well as core RAG1/2 but fails to cleave them (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cracking the DNA Code for V(D)J Recombination

Kim

Chuenchor²,

Chen³

et al. 2018

Molecular Cell

117

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Summary To initiate V(D)J recombination for generating the adaptive immune response of vertebrates, RAG1/2 recombinase cleaves DNA at a pair of recombination signal sequences, the 12- and 23-RSS. We have determined crystal and cryoEM structures of RAG1/2 with DNA in the pre-reaction and hairpin-forming complexes up to 2.75Å resolution. Both protein and DNA exhibit structural plasticity and undergo dramatic conformational changes. Coding-flank DNAs rotate, shift and deform extensively for nicking and hairpin formation. Two intertwined RAG1 subunits crisscross four times between the asymmetric pair of severely bent 12/23-RSS DNAs. Location-sensitive bending of 60° and 150° in 12- and 23-RSS spacers, respectively, must occur for RAG1/2 to capture the nonamers and pair the heptamers for symmetric double-strand breakage. DNA pairing is thus sequence-context dependent and structure specific, which partly explains the “beyond 12/23” restriction. Finally, catalysis in crystallo reveals the process of DNA hairpin formation and its stabilization by interleaved base stacking.

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Section: Discussionmentioning

confidence: 99%

Cracking the DNA Code for V(D)J Recombination

Kim

Chuenchor²,

Chen³

et al. 2018

Molecular Cell

117

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“…Questions remain as to whether RAG2 was part of the original transposon or whether it was an existing gene in the genome recruited to assist RAG1 in gene rearrangement 100,101 . Note that the RAGs are not used for VLR gene rearrangement in agnathans (see below), yet as mentioned, RAG1-like and RAG2-like genes have been found in the genomes of lower deuterostomes whose ancestors predated the vertebrates, such as sea urchins and amphioxi, where their functions, if any, are unknown 100,102 .…”

Section: Evolution Of Antigen Receptorsmentioning

confidence: 99%

A cold-blooded view of adaptive immunity

2018

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The adaptive immune system arose 500 million years ago in ectothermic (cold-blooded) vertebrates. Classically, the adaptive immune system has been defined by the presence of lymphocytes expressing recombination-activating gene (RAG)-dependent antigen receptors and the MHC. These features are found in all jawed vertebrates, including cartilaginous and bony fish, amphibians and reptiles and are most likely also found in the oldest class of jawed vertebrates, the extinct placoderms. However, with the discovery of an adaptive immune system in jawless fish based on an entirely different set of antigen receptors — the variable lymphocyte receptors — the divergence of T and B cells, and perhaps innate-like lymphocytes, goes back to the origin of all vertebrates. This Review explores how recent developments in comparative immunology have furthered our understanding of the origins and function of the adaptive immune system.

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“…In addition to RAG1 , RAG2 also was shown to have TE origins and several lines of evidence suggested that both RAG1 and RAG2 were domesticated from the same ancestral Transib element [26]. This evolutionary scenario has been solidified by a recent study that functionally characterized an active Transib element from the lancelet, a member of the cephalochordates, which lack V(D)J recombination [27]. This transposon, coined ProtoRAG , encodes both RAG1 - and RAG2 -like genes arranged just like their domesticated vertebrate homologs and flanked by TIRs that resemble the RSS and is able to undergo TIR-dependent transposition through a mechanism strikingly similar to RAG1/2-mediated DNA rearrangement [27].…”

Section: Conflicts Between Hosts and Pathogensmentioning

confidence: 99%

Transposable Element Domestication As an Adaptation to Evolutionary Conflicts

2017

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Transposable elements (TEs) are selfish genetic units that typically encode proteins that enable their proliferation in the genome and spread across individual hosts. Here we review a growing number of studies that suggest that TE proteins have often been coopted or ‘domesticated’ by their host as adaptations to a variety of evolutionary conflicts. In particular, TE-derived proteins have been recurrently repurposed as part of defense systems that protect prokaryotes and eukaryotes against the proliferation of infectious or invasive agents, including viruses and TEs themselves. We argue that the domestication of TE proteins may often be the only evolutionary path toward the mitigation of the cost incurred by their own selfish activities.

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Discovery of an Active RAG Transposon Illuminates the Origins of V(D)J Recombination

Cited by 170 publications

References 46 publications

Cracking the DNA Code for V(D)J Recombination

Cracking the DNA Code for V(D)J Recombination

A cold-blooded view of adaptive immunity

Transposable Element Domestication As an Adaptation to Evolutionary Conflicts

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