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.
|DiMenna, Lauren J; Yen, Wei-Feng; Nicolas, Laura et al. (2017) Cutting Edge: The Transcription Factor Sox2 Regulates AID Expression in Class-Switched B Cells. J Immunol 198:2244-2248|
|Drané, Pascal; Brault, Marie-Eve; Cui, Gaofeng et al. (2017) TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature 543:211-216|
|Kunimoto, Hiroyoshi; McKenney, Anna Sophia; Meydan, Cem et al. (2017) Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells. Blood 129:1779-1790|
|Chen, Chun-Chin; Kass, Elizabeth M; Yen, Wei-Feng et al. (2017) ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair. Proc Natl Acad Sci U S A 114:7665-7670|
|Vaidyanathan, Bharat; Chaudhry, Ashutosh; Yewdell, William T et al. (2017) The aryl hydrocarbon receptor controls cell-fate decisions in B cells. J Exp Med 214:197-208|
|DiMenna, Lauren J; Chaudhuri, Jayanta (2016) Regulating infidelity: RNA-mediated recruitment of AID to DNA during class switch recombination. Eur J Immunol 46:523-30|
|Balestrini, Alessia; Nicolas, Laura; Yang-Lott, Katherine et al. (2016) Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model. Mol Cancer Res 14:185-95|
|Pucella, Joseph N; Yen, Wei-Feng; Kim, Myoungjoo V et al. (2015) miR-182 is largely dispensable for adaptive immunity: lack of correlation between expression and function. J Immunol 194:2635-42|
|Zheng, Simin; Vuong, Bao Q; Vaidyanathan, Bharat et al. (2015) Non-coding RNA Generated following Lariat Debranching Mediates Targeting of AID to DNA. Cell 161:762-73|
|Matthews, Allysia J; Husain, Solomon; Chaudhuri, Jayanta (2014) Binding of AID to DNA does not correlate with mutator activity. J Immunol 193:252-7|
Showing the most recent 10 out of 22 publications