The process of somatic hypermutation (SHM) of immunoglobulin (Ig) genes takes place in B lymphocytes after specific interaction with antigen and T lymphocytes. SHM has several steps and requirements. In our working model, the cell needs to produce a postulated mutator factor (MuF) which has to be targeted to Ig genes by transcription. The MuF may act as an endonuclease that creates a nick or double-strand break in the gene. The nick/break is believed to be repaired in an error-prone fashion, creating mutations. Mismatch repair may remove some of the mutations or fix them by """"""""correcting"""""""" the wildtype nucleotide on the complementary DNA strand. Cell replication propagates the mutations to one or both daughter cells. The following investigations are proposed: 1) What is the role of a specific E-box site in SHM? Such a transactivator site was found to enhance SHM without enhancing transcription. 2) How does the position of nucleosomes affect the SHM process? SHM occurs in clusters that suggest involvement of nucleosomes in the targeting of mutations. Mono-nucleosomal DNA from a mutable mouse transgene will be tested for phasing of nucleosomes over the SHM target relative to mutations. 3) Can a double-strand DNA break induce SHM? The possibility will be tested that introduction of a double strand break into a SHM target gene induces mutations without the need for the initiating events of SHM. 4) When during the cell cycle does SHM occur? It is still unknown if DNA replication of the genome is involved directly in SHM, and/or if recombination is required. Single cells will be isolated at various cell cycle stages and screened for molecular intermediates consistent with an ongoing mutation process. 5) Which mRNAs are modified by the cytidine deaminase, AID, in mutating B lymphocytes? The cytosine deaminase, AID, is required for SHM. The potential target mRNAs will be identified. The planned experiments are important for learning how the varied repertoire of Ig genes is created with the potential to react against any foreign antigenic determinant, including tumor cell antigens. Somatic hypermutation has also been implicated in autoimmune diseases. Furthermore, many B cell lymphomas arise apparently as a consequence of the somatic mutation process. It is likely that understanding the components involved in somatic mutation will aid in understanding the genetic and environmental causes of autoimmunity, and the treatment of infectious diseases and tumors. Surprisingly, the BCL6 proto-oncogene is highly mutated in human memory B cells. This is likely to be involved in tumorigenesis. Thus, a better understanding of the somatic mutation process may aid in the understanding and perhaps prevention, diagnosis and treatment of human B lymphomas related to BCL6 expression.
| Kodgire, Prashant; Mukkawar, Priyanka; North, Justin A et al. (2012) Nucleosome stability dramatically impacts the targeting of somatic hypermutation. Mol Cell Biol 32:2030-40 |
| Tanaka, Atsushi; Shen, Hong Ming; Ratnam, Sarayu et al. (2010) Attracting AID to targets of somatic hypermutation. J Exp Med 207:405-15 |
| Ratnam, Sarayu; Bozek, Grazyna; Nicolae, Dan et al. (2010) The pattern of somatic hypermutation of Ig genes is altered when p53 is inactivated. Mol Immunol 47:2611-8 |
| Storb, Ursula; Shen, Hong Ming; Nicolae, Dan (2009) Somatic hypermutation: processivity of the cytosine deaminase AID and error-free repair of the resulting uracils. Cell Cycle 8:3097-101 |
| Shen, Hong Ming; Bozek, Grazyna; Pinkert, Carl A et al. (2008) Expression of AID transgene is regulated in activated B cells but not in resting B cells and kidney. Mol Immunol 45:1883-92 |
| Longerich, Simonne; Orelli, Brian J; Martin, Richard W et al. (2008) Brca1 in immunoglobulin gene conversion and somatic hypermutation. DNA Repair (Amst) 7:253-66 |
| Longerich, Simonne; Meira, Lisiane; Shah, Dharini et al. (2007) Alkyladenine DNA glycosylase (Aag) in somatic hypermutation and class switch recombination. DNA Repair (Amst) 6:1764-73 |
| Storb, Ursula; Shen, Hong Ming; Longerich, Simonne et al. (2007) Targeting of AID to immunoglobulin genes. Adv Exp Med Biol 596:83-91 |
| Shen, Hong Ming (2007) Activation-induced cytidine deaminase acts on double-strand breaks in vitro. Mol Immunol 44:974-83 |
| Shen, Hong Ming; Tanaka, Atsushi; Bozek, Grazyna et al. (2006) Somatic hypermutation and class switch recombination in Msh6(-/-)Ung(-/-) double-knockout mice. J Immunol 177:5386-92 |
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