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. Author manuscript; available in PMC: 2019 Apr 1.
Published in final edited form as: Nat Rev Immunol. 2019 Apr;19(4):231–242. doi: 10.1038/s41577-019-0135-6

Fig. 4:|. ordered assembly of antigen receptor genes.

Fig. 4:|

Antigen receptor gene assembly at several loci is ordered inter-allelically, such that one allele rearranges at a time. Once completed, the rearrangement is tested to determine whether it is productive before rearrangement at the alternative allele occurs. This inter-allelic ordering is critical for enforcing allelic exclusion. Antigen receptor gene assembly is also intra-allelically ordered. After a rearrangement is initiated on one allele, the initiation of additional rearrangements on the same allele must be prevented. Cleavage events at an antigen receptor loci mediated by recombination-activating gene (RAG) proteins are regulated by accessibility of the loci. However, once RAG double-strand breaks (DSBs) are made, the non-canonical DNA damage response (ncDDR) participates in enforcing both inter-allelic and intra-allelic ordering to prevent additional RAG DSBs from being generated until the initial rearrangement has been completed and tested to determine whether it encodes a functional antigen receptor gene. ATM, ataxia telangiectasia mutated.