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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072194-08
Application #
9172233
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Nasseri, M Faraz
Project Start
2009-07-01
Project End
2019-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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
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
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; Zheng, Simin; DiMenna, Lauren J et al. (2014) Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair. Adv Immunol 122:1-57
Matthews, Allysia J; Husain, Solomon; Chaudhuri, Jayanta (2014) Binding of AID to DNA does not correlate with mutator activity. J Immunol 193:252-7
Vuong, Bao Q; Herrick-Reynolds, Kayleigh; Vaidyanathan, Bharat et al. (2013) A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination. Nat Immunol 14:1183-9
Nicolás, Laura; Chaudhuri, Jayanta (2013) 4C-ing the Igh Landscape. Immunity 39:199-201
Kumar, Ritu; DiMenna, Lauren; Schrode, Nadine et al. (2013) AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes. Nature 500:89-92
Vuong, Bao Q; Chaudhuri, Jayanta (2012) Combinatorial mechanisms regulating AID-dependent DNA deamination: interacting proteins and post-translational modifications. Semin Immunol 24:264-72

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