Mature B-lymphocytes undergo class switch recombination (CSR), a deletional-recombination reaction that replaces the constant region of the immunoglobulin (Ig) molecule for one of a set of downstream constant region genes. This changes the class of the expressed antibody from IgM to IgG, IgE or IgA, each of which has distinct effector functions. CSR occurs within and requires large repetitive sequences termed switch (S) regions that precede the constant region genes. CSR is initiated by AID (activation induced deaminase), a single-strand DNA-specific deaminase, that introduces U:G mismatches in transcribed S regions. Subsequent processing by components of base excision repair and mismatch repair pathways introduces DNA double- stranded breaks (DSBs) in S regions. DSBs between two distinct S regions are synapsed and then ligated by end-joining. DSBs serve as obligatory intermediates of CSR; however, DSBs also constitute one of the most toxic lesions that can occur in a cell. A single unrepaired DSB can lead to cell death or can participate in chromosomal translocations, the hallmarks of many types of cancer, including lymphomas. Thus, CSR requires not only the generation but also efficient repair of DSBs. In this proposal we test the hypothesis that phosphorylation of AID plays an essential role in the generation of DSBs. We also explore the hypothesis that the DNA damage sensor ATM participates in inducing AID phosphorylation and repair of DSBs during the process. Impaired CSR leads to impaired ability to respond to pathogens while aberrant CSR is one of the major underlying factors in the ontogeny of B cell lymphomas. Our studies will thus have major impact on both immunodeficiency syndromes and B cell lymphomagenesis.
Class switch recombination is essential for human B cells to mount an efficient immune response to invading pathogens. A failure to undergo class switching leads to immunodeficiency syndromes in humans. On the other hand, aberrant class switch recombination is directly responsible for the ontogeny of mature B cell lymphomas, the most common lymphomas in humans. Mechanistically elucidating class switch recombination, the focus of this proposal, is thus related to both human immunodeficiencies and B cell lymphomas.
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