Elements regulating somatic hypermutation of an immunoglobulin κ gene: Critical role for the intron enhancer/matrix attachment region

Biased dA/dT somatic hypermutation as regulated by the heavy chain intronic iEμ enhancer and 3′Eα enhancers in human lymphoblastoid B cells

“…Mutation rate of PCMV-VDJ-iEµ-Cγ1 is four-fold greater than that of P-VDJ-iEµ-Cγ1, which is consistent with previous findings that the Ig V H promoter is not essential for SHM and can be functionally replaced by a heterologous promoter (Betz et al, 1994;TumasBrundage and Manser, 1997). SHM of V H 1-DXP′1-J H 5 DNA was differentially regulated by the iEµ, hs1,2 and hs3-hs4 enhancers.…”

“…In addition, accumulating evidence suggests that mutations can be introduced by the same translesion DNA polymerases (Zan et al, 2001;Diaz and Casali, 2002;Diaz and Lawrence, 2005) while repairing DNA breaks, including double stranded DNA breaks (DSBs) involving resected ends generated through AID-dependent DNA deamination (Bross et al, 2000;Papavasiliou and Schatz, 2000;Wu et al, 2003;Zan et al, 2003;Nagaoka et al, 2005;Xu et al, 2005). SHM depends on V gene transcription (Peters and Storb, 1996;Fukita et al, 1998), as suggested by the greatly diminished frequency of mutations in the IgH locus when the V gene promoter is removed (Fukita et al, 1998), and conversely, by unchanged level of SHM in V regions if the endogenous promoter is replaced with a transcriptionally active heterologous promoter (Betz et al, 1994;). B cell specific V H gene transcription is regulated by the IgH intronic enhancer (iEµ), which is located 5′ of Sµ (Banerji et al, 1983;Gillies et al, 1983) and recruits multiple transcription factors, including proteins of the E-box and POU families (Ernst and Smale, 1995).…”

The c-MYC allele that is translocated into the IgH locus undergoes constitutive hypermutation in a Burkitt's lymphoma line

“…A connection between mutability and transcription has been noted in several studies (Betz et al, 1994;Peters and Storb, 1996;Goyenechea et al, 1997;Fukita et al, 1998) and Peters and Storb (1996) have proposed that transcriptional pausing may play a role in hypermutation. Transcriptional pause sites in c-MYC are amongst the best characterized of those in mammalian RNA polymerase II transcription units (Bentley and Groudine, 1986;Chung et al, 1987;Kerppola and Kane, 1988;Strobl and Eick, 1992;Keene et al, 1999).…”

“…The V gene, whilst the physiological target of the mutation, is not needed for mutation recruitment: other sequences can be mutated in its place (Yelamos et al, 1995). Mutation recruitment depends upon the immunoglobulin transcription regulatory elements (Betz et al, 1994) with the location of the mutation domain being de®ned by the position of the transcription start site (Peters and Storb, 1996;Rada et al, 1997;Tumas-Brundage and Manser, 1997). Whilst the immunoglobulin loci are certainly the preferred targets of the hypermutation, the process is not wholly exclusive to them: BCL-6 (but not several other genes analysed) has been found to be a natural target for the hypermutation process ± albeit at a much reduced mutation rate (Migliazza et al, 1995;Pasqualucci et al, 1998;Shen et al, 1998).…”

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

“…The striking influence of nucleosome composition on Ig diversification does suggest to us the interesting possibility that local physical constraints on the locus could collaborate with H3.3‐containing nucleosomes to promote ssDNA formation during transcription by enhancing the probability that negative supercoiling induces ssDNA bubbles. Such a model could potentially help explain the role of the matrix attachment regions in promoting strong Ig diversification (Betz et al , 1994). It will therefore be interesting in future studies to determine the extent to which genomic structural features allow H3.3 to influence ssDNA exposure and mutagenesis genome‐wide.…”