DNA Damage Responses in B Cell Development

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DESCRIPTION (provided by applicant): B lineage cells of the immune are unique in their ability to undergo developmentally programmed DNA double strand breaks (DSB) within their immunoglobulin loci during an immune response in order to generate functional antibodies in a process termed class switch recombination (CSR). Switching B cells thus offer an excellent model to study cellular responses to physiologic DSB. B cells undergoing CSR trigger the DNA damage response (DDR) pathway, which signals cells to pause and repair DNA breaks, or if unable to resolve the damage to then undergo apoptosis. The DDR pathway is the initial cellular response to DNA damage, which is activated early in tumorigenesis but is frequently lost during progression to cancer. Disruption of the DDR pathway during CSR leads to impaired immunoglobulin switching in B cells and to chromosomal translocations involving the IgH locus. The ataxia-telangiectasia mutated gene (ATM) is the key coordinator of sensing and responding to DNA damage. B cells deficient for ATM have impaired CSR and frequently generate chromosomal translocations involving the immunoglobulin heavy chain locus. In this regard, ATM alterations have been detected in many lymphoid malignancies. The exact role of ATM in maintaining genomic stability in B lineage cells remains unknown. In this proposal we seek to develop methods to study the mechanisms that regulate ATM recruitment to programmed DNA breaks in B cells undergoing class switching. Localization and molecular assessment of the DSB repair complex will elucidate the components of the DDR during CSR. In addition we will examine defined populations of B cells participating in an active immune response to determine the specific populations in which ATM and other members of the DDR are recruited to the IgH locus. In our second aim, we will further test the exact DNA sequences that facilitate recruitment of ATM to the IgH locus. Taken together, these studies will further define the mechanisms that regulate the maintenance of genomic stability in ATM-deficient B cells, providing insights towards the development of therapeutic targets. PUBLIC HEALTH RELEVANCE: B cell lymphoma is a major cause of death in patients with ataxia-telangiectasia. The studies in this proposal seek to understand the basic mechanisms that promote oncogenic events B cells, which is also applicable towards other cancers that develop in AT patients. These findings may lead to the development of novel and rational therapeutic targets for cancer in patients with AT.