Figure 6.

Proposed model for rearrangement events in the Ku^−/−p53^−/− and Ku^−/−p53^−/− Rad54^−/− pro-B cell lymphomas. RAG proteins initiate DNA DSB at the IgH D and J gene segments (step 1). Due to the absence of the Ku holoenzyme, the DSB cannot be efficiently and correctly repaired. The IgH DSB attacks sequences on chromosome 15. In scenario A, this results in a DSB in which the telomeric fragment of chromosome 15 is translocated to chromosome 12 while repair of the lesion on chromosome 15 occurs through a break-induced replication pathway such that sequences from chromosome 12 are copied to the der(15)_a (steps 2a and 3a). In scenario B, c-myc is copied to der(12)_b without disruption of the normal chromosome 15 (steps 2b and 3b). In both cases, however, the derivative chromosome is left with a persistent DSB. The broken chromatid is replicated during S-phase (step 4) and the free chromatid ends are ligated together to form a bridge (step 5). During mitosis when the chromatids are separated, a tug-of-war ensues resulting in the breaking of the derivative chromosome (step 6). Depending on where the break occurs, one cell may contain a chromosome with amplification of the genes as an inverted repeat (step 7). Because this chromosome still does not have a telomere sequence, the cycle continues until a telomere is captured (step 8).