Switch recombination sites

The conservation of repetitive elements in S regions has led to the working hypothesis that such elements play a central role in the switch rearrangement. About 20 DNA sequences of the recombination junctions of various class-switches have been determined in order to get information on the sequence requirements of switch recombination [63-80,83,85], Comparison of these sequences makes it clear that the enzymes involved in class-switching do not recognize an obviously well conserved sequence. 

Switch recombination sites share only little and patchy sequence homology at variable distances from the actual breakpoint of recombination. Sequence motifs such as GAGCT and GGGGT [79] or YAGGTTG [84] have been postulated to play a specific role in switch recombinase recognition. However, these hypotheses 

In the SM region, switch recombination may occur everywhere between the 3 end of a VHDJH segment and the 5 end of the gene [36,86]. Switch recombinations also occur, but less frequently, within that portion of SM in which the many short repeats are found. This region is the one which frequently undergoes in vitro recombination catalyzed by Escherichia coli extracts [87]. Deletions which seem to precede the recombination of to another S region (see Section 4.1.) are frequently observed within SM (Fig. 2). These deletions are not artefacts of molecular cloning ([74], and own results) and seem to be characteristic of IgH loci which are poised for switch recombination. 

It would seem from the present findings that the specificity of class-switch recombination is not mediated by consensus sequences in the S regions. It is more likely that the control of class-switching operates at the level of chromatin structure which may be influenced by repetitive sequences. 

The construction of switch models suffers from the lack of information on the early steps of switching. Nevertheless, one can try to sketch a simple picture of the classswitching process in mammalian B cells (Fig. 3). 

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Dunnick, W., Hertz, G.Z., Scappino, L., Gritzmacher, C. (1993). DNA sequences at immunoglobulin switch region recombination sites. Nucleic Acids Res. 21, 365-372. 

Katzenberg, D.R. Birshtein, B.K. (1988). Sites of switch recombination in IgG2b- and IgG2a-producing hybridomas. J. Immunol. 140,3219-3227. 

Class switch recombination is also found to take place in plasmacytoma and hy-bridoma cells. These rare variant cells can be detected in many cell lines at frequencies of 1(T4 to 1CT7 (see Section 2.2.5.). In all cases analysed so far intermediate CH genes have been deleted from the active IgH loci. Frequently, however, the recombination sites were outside of the switch region - most drastically in the IgD variants (see review [C]), there being no switch sequence in front of C5 [56], This could be the reason why in normal B cells switching from IgM to IgD is rare upon activation. 

The switch is accomplished by periodic inversion of a segment of DNA containing the promoter for a flagellin gene. The inversion is a site-specific recombination reaction (see Fig. 25-39) mediated by the Hin re-combinase at specific 14 bp sequences (hix sequences)... 

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