Proceedings of the National Academy of Sciences of the United States of America, 14 July 2015, Vol.112(28), pp.8579-83
The variable domains of Ig and T-cell receptor genes in vertebrates are assembled from gene fragments by the V(D)J recombination process. The RAG1-RAG2 recombinase (RAG1/2) initiates this recombination by cutting DNA at the borders of recombination signal sequences (RSS) and their neighboring gene segments. The RAG1 protein is also known to contain a ubiquitin E3 ligase activity, located in an N-terminal region that is not strictly required for the basic recombination reaction but helps to regulate recombination. The isolated E3 ligase domain was earlier shown to ubiquitinate one site in a neighboring RAG1 sequence. Here we show that autoubiquitination of full-length RAG1 at this specific residue (K233) results in a large increase of DNA cleavage by RAG1/2. A mutational block of the ubiquitination site abolishes this effect and inhibits recombination of a test substrate in mouse cells. Thus, ubiquitination of RAG1, which can be promoted by RAG1's own ubiquitin ligase activity, plays a significant role in governing the level of V(D)J recombination activity.
Diversification ; Immunoglobulin ; Ubiquitin ; Ubiquitination ; V(D)J Recombination ; Homeodomain Proteins -- Metabolism
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