Upon encountering antigens, mature B cells express activation induced cytidine deaminase (AID) and undergo immunoglobulin heavy chain (Igh) class switch recombination (CSR) and somatic hypermutation (SHM). CSR proceeds through the obligate generation of DNA double strand breaks (DSBs), which constitute one of the most toxic lesions that can occur in a cell. A single unrepaired DSB can cause cell death or potentiate chromosomal translocations that are hallmarks of many types of cancer, including lymphomas. Thus, mechanisms that promote generation of DSBs and facilitate DSB repair are intergral to both immunity and preservation of genomic integrity. In this proposal we test the notion that single proteins can coordinate both DSB formation and mediate end-joining to efficiently generate and repair DSBs. We test the hypothesis that the nucleosomal remodeling protein CHD4 co-ordinates generation and repair of Igh DSBs (aim 1) and the C- terminus of AID mediates efficient DNA repair of Igh DSBs (aim 2). Successful completion of the experiments will have far reaching implications in our understanding of both B cell immunity and B cell lymphomas.
Class switch recombination and somatic hypermutation is essential for B cell-mediated immunity as its failure leads to immunodeficiency syndromes in humans. On the other hand, aberrant class switch recombination and somatic hypermutation is directly responsible for the ontogeny of mature B cell lymphomas, the most common lymphoma in humans. The goal of this application is to understand the mechanisms that promote genomic alterations in B cells to promote immunity while simultaneously preventing collateral damage. The proposal is therefore directly related to both human immunodeficiencies and B cell oncogenesis.
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