Mechanistic aspects of lymphoid chromosomal translocations

Abstract

Chromosomal translocations require double-strand breakage at two sites, followed by joining of the ends. The joining is usually done by nonhomologous DNA end-joining, though homologous recombination and single-strand annealing play roles in cases where there is homology. The mechanism of breakage can be more difficult to understand at sites other than the antigen receptor loci. Some breakage events in pre–B or pre–T cells are due to the RAG proteins recognizing heptamer/nonamer-like sequences, but most breaks are not. Rather, some of these breaks are due to RAG nicking at non–B DNA conformations. Translocation events in mature B cells, when RAGs are not expressed, may be due to the activation-induced deaminase (AID). But AID only acts on single-stranded DNA, and it is not yet clear how this single-stranded DNA arises at some transcribed sites and not others. During the physiologic process of class switch recombination, R-loops form at transcribed class switch regions, thereby accounting for how single strandedness is facilitated at these sites of AID action.