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Apoptosis

Apoptosis

Rearrangement involving switching signals

Figure 1 The generation of a productive immune receptor gene is linked to the activity of the recombinase complex. The multi-step rearrangements of the immune locus that takes place during maturation of lymphocytes provides the 'window' during which error-prone recombination may result in a translocation that will allow the clonal proliferation of the cell that has undergone such a translocation. It is possible that normal monitors of the differentiation process that determine the suitability of the lymphocyte at each step also need to be neutralized in the cell with an immune gene translocation in order to resist apoptosis.

way, which again is intralocus, carries out the juxtaposition of the various constant regions to the rearranged VDJ region, allowing the Ig molecule to switch from IgM to any other class. A third pathway that provides additional diversity to the immune molecules is the hypermutation pathway.

Several factors subscribe to the catalysis of these recombination mechanisms. The recombinase machinery interacts with signal sequences on the two segments that need to be cut and pasted, which consist of a heptamer, defined by the consensus sequence CACAGTG, and a nonamer (GGTTTTGT) present on each site. It seems reasonable that the substrates for the recombination should be accessible to the recombinase enzymes, thus it is likely that structural features, e.g. the chromatin structure, will mechanistically influence the recombination pathway.

Error-prone recombination: cause of chromosomal aberrations

Given the high frequency of all recombinational events in the lifetime of an organism it is likely that in some instances errors in the recombinase machinery will lead to interlocus rather than intralocus recombination. The time window of such errors would, of necessity, mirror the time window in the cell lineages where recombinase machinery is active (Figure 1). The recombinational events that are more likely to result in such mistakes include the juxtaposition of the D to the J regions, the recombination of the V and the rearranged DJ region and the switch recombinations.

The occurrence of interlocus recombination within the same chromosome but involving relatively distant sites has been documented for the inversions of chromosome 14, between the immunoglobulin heavy chain and the TCRa genes, and of chromosome 7, involving the TCR0 and y genes. Interlocus recombination that involves two chromosomes has also been documented for the translocations that involve chromosomes 7 and 14 where there is a VDJ recombination that juxtaposes V7 to DJ8 or VDS to J7. It has been suggested that this interchromosomal event may occur at a frequency as high as 1 X 10

The possibility that the presence of a heptamer sequence alone may in some circumstances catalyze the locus to act as a substrate of recombinase albeit at a low frequency, increases the likelihood of recombination involving immune genes and nonimmune partners.

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