Transposons to V(D)J Recombination: Evolution of the RAG Reaction

Abstract

Evolutionarily, how RAG endonucleases in vertebrate immune systems could shed dangerous transposon-like propensities, and instead, support the organized assembly of antigen receptor variable domains, has been unclear. Recent structural work by Schatz and colleagues (Nature, 2019) identifies features of the RAG endonuclease deemed to be key in supporting this critical change in vertebrate advancement.

Figure 1.. Comparison of Transposons and V(D)J Recombination.

Transposons in both prokaryotes and eukaryotes can be described with the diagram on the left portion of the figure. The blue triangles depict the terminal inverted repeat (TIR) at the edges of the transposable element (TE). A transposase, often encoded in a gene between the TIRs, is an enzyme that cuts the DNA at the edges of the TIRs, leaving behind the donor DNA (designated a, b). The DNA with a TIR at each end can reinsert in a new DNA site (c, d). The lancelot TE functions in a manner shown on the left – even though the TIRs are similar to the V(D)J recombination signal sequences (RSSs) in jawed vertebrates, and even though the orthologs for RAGs are similar in many ways. The study from the Schatz laboratory shows that two key changes in the RAG proteins are important for converting the reaction to the one shown on the right [6]. The V(D)J recombination reaction involves hairpin formation of the V and J coding ends. The RSS ends do not reinsert into the genome at any significant frequency. The two RSS ends become joined to form a circle [in deletional V(D)J recombination]. All of the joining events on the right are carried out by the nonhomologous DNA end joining (NHEJ) pathway. Some of the joining events on the left involve NHEJ components as well, or can involve repair by homologous recombination using an intact donor elsewhere in the genomes. Abbreviation: aa, amino acid.