UNEQUAL SISTER CHROMATID EXCHANGE ACTS ON Ig GENES

Though the phenomenon of sister chromatid exchange (SCE) 1 has now been known for over thirty years (1-3), its biological role(s) remains poorly defined (see ref. 4). The greatest number of observations of SCE have come from cytogenetic studies using agents such as [3H]thymidine or 5-bromodeoxyuridine to label sister chromatids differentially and observe their exchange. Such studies demonstrate a marked increase in SCE after mutagenesis of somatic cells with certain agents (5-7), or in cells from patients with Bloom's syndrome (8), a disorder characterized by a unique type of chromosomal instability. These observations suggest that SCE is, in some way, involved in normal processes of DNA repair (5, 6). There is also genetic evidence for unequal SCE in germ line cells of Drosophila melanogaster. In studies by Ritossa (9) and Tartof (10), unequal SCE was induced by mutations (e.g. bobbed) impairing ribosomal RNA (rRNA) expression, and resulted in a genetically stable increase or decrease in rRNA gene copy number. Those flies showing a stable increase in rRNA gene copy number were restored to the wild type phenotype. Unequal SCE may also be the mechanism of DNA rearrangements that alter gene expression in mammalian cells of the B lymphoid lineage. Such cells undergo a DNA rearrangement during differentiation in vivo or in vitro known as the Ig heavy (H) chain class switch (reviewed in refs. 11 and 12). In this type of DNA rearrangement, a previously assembled H chain variable region (V.) gene is rearranged from the region 5' of the expressed H chain constant region (CH) gene to the region 5' of another C. gene to be expressed. There is evidence that this usually occurs on a single chromosome and in an order corresponding to the 5' to 3' order of C. genes along the chromosome (although skips may occur). The loss or deletion of C. genes upstream (5') of the one expressed after an H chain class switch has often been interpreted to mean that the switch occurs by looping out and deletion of DNA on a single chromatid or chromosome. Other studies Show that the 5' to 3' order of C. genes may be altered before or during switching, and that switching involves an asymmetric cell division: these results support SCE as the mechanism of class switching.