Class switch recombination (CSR) is the process by which B cells alter the effector function properties of their Ig molecules. The decision to switch to a particular Ig isotype is determined primarily by the mode of B cell activation and cytokine exposure. More recent work indicates that the likelihood or probability of switching increases with successive cell divisions and is largely independent of time. We have analyzed different molecular features of CSR using cell division as a reference point in an attempt to gain insight into the mechanism of division-linked switching. Our results indicated that the accessibility of Ig heavy chain constant regions targeted for CSR was established after the cells had undergone a single cell division and did not vary significantly with subsequent cell divisions. In contrast, expression of activation-induced cytidine deaminase (AID) mRNA was found to increase with successive divisions, exhibiting a striking correlation with the frequency of CSR. Levels of AID in a given division remained constant at different time points, strongly suggesting that the regulation of AID expression was division-linked and independent of time. In addition, constitutive AID expression from a transgene accelerated division-linked CSR. Thus, we propose that the division-linked increase in AID expression provides an underlying molecular explanation for division-linked CSR.B lymphocyte ͉ cell division C lass switch recombination (CSR) is a region-specific DNA recombination mechanism that occurs by exchanging the currently expressed Ig heavy chain constant region (C H ) for another downstream C H region. CSR enables B cells to alter the effector properties of their Ig molecules without altering their antigen specificity. Conceptually, class switching can be divided into three stages of targeting, cleavage, and DNA repair͞rejoining, with specific molecular events associated with each stage. For example, cytokine-induced C H region accessibility is marked by acetylation of histone proteins and germ-line transcription across targeted switch (S) regions (1, 2), highly repetitive sequences upstream of each C H gene except C␦. S region cleavage involves the introduction of DNA lesions in S regions targeted for recombination (3-5), and finally, the rejoining of the cleaved ends requires a number of ubiquitously expressed DNA repair factors. In addition, CSR absolutely requires the activity of the activation-induced cytidine deaminase (AID) (6). Although originally speculated to be an RNA-editing enzyme, recent data strongly suggest that AID functions as a DNA deaminase (7,8), acting in the context of transcription to deaminate cytosines on single-stranded DNA templates within S regions before the introduction of double-stranded lesions (9-11).Class switching to particular Ig isotypes in vivo is determined by a combination of exposure to pathogenic stimuli, T cell help, and particular cytokines (reviewed in ref. 12). Induction of switching to all of the different Ig isotypes can be recapitulated ex vivo, which...
A secondary structure in the nascent RNA followed by a trail of U residues is believed to be necessary and sufficient to terminate transcription. Such structures represent an extremely economical mechanism of transcription termination since they function in the absence of any additional protein factors. We have developed a new algorithm, GeSTer, to identify putative terminators and analysed all available complete bacterial genomes. The algorithm classifies the structures into five classes. We find that potential secondary structure sequences are concentrated downstream of coding regions in most bacterial genomes. Interestingly, many of these structures are not followed by a discernible U-trail. However, irrespective of the nature of the trail sequence, the structures show a similar distribution, indicating that they serve the same purpose. In contrast, such a distribution is absent in archaeal genomes, indicating that they employ a distinct mechanism for transcription termination. The present algorithm represents the fastest and most accurate algorithm for identifying terminators in eubacterial genomes without being restricted by the classical Escherichia coli paradigm.
Chromosomal translocations involving immunoglobulin heavy chain (Igh) switch regions and an oncogene such as Myc represent initiating events in the development of many B cell malignancies. These translocations are widely thought to result from aberrant class-switch recombination. To test this model, we measured translocations in mice deficient in activation-induced cytidine deaminase (AID) that lack class-switch recombination. We found that AID made no measurable contribution to the generation of initial translocations, indicating that the intrinsic fragility of the switch regions or a pathway unrelated to AID is responsible for these translocations. In contrast, the outgrowth of translocation-positive cells was dependent on AID, raising the possibility that AID is important in tumor progression, perhaps by virtue of its mutagenic properties.
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