Structural insights into the evolution of the RAG recombinase

Chang Liu, Yuhang Zhang, Catherine C. Liu, David G. Schatz

Research output: Contribution to journalReview articlepeer-review


Adaptive immunity in jawed vertebrates relies on the assembly of antigen receptor genes by the recombination activating gene 1 (RAG1)–RAG2 (collectively RAG) recombinase in a reaction known as V(D)J recombination. Extensive biochemical and structural evidence indicates that RAG and V(D)J recombination evolved from the components of a RAG-like (RAGL) transposable element through a process known as transposon molecular domestication. This Review describes recent advances in our understanding of the functional and structural transitions that occurred during RAG evolution. We use the structures of RAG and RAGL enzymes to trace the evolutionary adaptations that yielded a RAG recombinase with exquisitely regulated cleavage activity and a multilayered array of mechanisms to suppress transposition. We describe how changes in modes of DNA binding, alterations in the dynamics of protein–DNA complexes, single amino acid mutations and a modular design likely enabled RAG family enzymes to survive and spread in the genomes of eukaryotes. These advances highlight the insight that can be gained from viewing evolution of vertebrate immunity through the lens of comparative genome analyses coupled with structural biology and biochemistry.

Original languageEnglish (US)
Pages (from-to)353-370
Number of pages18
JournalNature Reviews Immunology
Issue number6
StatePublished - Jun 2022
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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