The Role of DNA Repair in Somatic Hypermutation of Immunoglobulin Genes

I mmunoglobulin (Ig) genes are first modified through the V(D)J (V, variable; D, diversity; J, joining) recombina-tion process in pre–B cells. The Rag1/Rag2-dependent V(D)J recombination generates a large repertoire of B lym-phocytes, each expressing a unique antibody molecule. Rearranged Ig genes are further modified by the somatic hypermu-tation process in activated germinal center B lymphocytes. Through somatic hypermutation, point mutations are introduced into Ig genes at the average frequency of one mu-tation/10 2 base pairs. After the mutation process, B cells with nucleotide substitutions resulting in higher affinity an-tibody are selected for proliferation and differentiation into memory or plasma cells. Several molecular features are characteristic of somatic hypermutation (1). The mutations are mostly single substitutions , very rarely deletions or insertions. Hot spots of mutation have been observed and of these most notable are the AGY trinucleotides. Somatic mutation of Ig genes is confined to a region of ‫ف‬ 1.5 kb downstream of the variable region gene promoter. The constant region exon, which is separated from the variable region exon by several kb of intron, is usually not targeted for mutation. There also appears to be a strand bias and A Ͼ T bias (2). Which strand is the preferential substrate of the mutation process has, however, not been determined. Further insights into the mechanism of somatic hypermutation were made possible by the use of transgenic mice bearing Ig genes with various modifications. A transgenic construct with deletion of the Ig ␬ intronic enhancer no longer mutates (3). Surprisingly , insertion of an Ig promoter just upstream of the constant region exon results in mutations in the constant region in addition to the variable region, but sparing of the region in between (4). The link between promoter proximity and mutation targeting, as well as the evidence of strand bias and the need for enhancers, strongly suggests that there is a link between transcription and Ig gene so-matic hypermutation (4). However, how a mechanism linked to RNA transcription introduces point mutations into Ig genes is still largely a mystery, although a role for RNA polymerase pausing and deposition of a mutator factor with sequence preferences is suggested by recent findings manuscritp submitted for publication). Several proposals have been made of how DNA repair might be involved in the somatic hypermutation process. On the one hand, DNA repair may be used to induce the mutations. The transcription-linked model proposed by Peters and …