Antibody (immunoglobulin, Ig) class switch recombination (CSR) is an essential mechanism for the diversification of humoral immune response through efficient generation of antibody isotypes that mediate elimination of pathogens. CSR is a programmed deletional recombination event between DNA double strand breaks (DSBs) at switch (S) regions in the Ig heavy chain gene locus (Igh). These DSBs are initiated by the mutagenic enzyme, activation-induced cytidine deaminase (AID), which preferentially localizes at Igh loci but also exhibits off-target activity in other genomic regions including proto-oncogenes. Hence, DSBs initiated by AID in off-target regions of the genome can readily lead to aberrant recombination events and chromosome translocations between the Igh locus and oncogenes if not correctly repaired. Indeed, such genomic aberrations are a hallmark of B-cell malignancies. However the molecular mechanisms that define how B-cells control the repair of DNA lesions initiated by AID are poorly understood. Accordingly the goal of our research proposal is to characterize novel molecular mechanisms we have identified that regulate the repair of DNA lesions initiated by AID during CSR. We recently discovered that the telomeric protein TRF2, which is essential for protecting chromosome ends from DNA repair activity, is also needed for CSR. Here we propose to extend our studies to identify and characterize the molecular mechanisms utilized by TRF2 to control the CSR via the following specific aims: 1. Identify and characterize the specific DDR proteins regulated by TRF2 during CSR. 2. Dissect the molecular mechanisms used by TRF2 to control DNA repair during CSR. 3. Elucidate how TRF2 interacts with the Igh locus during CSR. Taken together, these studies will provide specific details into a novel mechanism that regulates immune diversification in B-cells and the maintenance of the genome stability during AID activation.
Antibody class switch recombination (CSR) is an essential mechanism for the diversification of humoral immune response and the elimination of many pathogens such as viruses and bacteria from our bodies. The goal of this research project is to characterize novel molecular mechanisms we have identified that regulate CSR, which may enable the design of novel therapeutic strategies for controlling humoral immune responses.
|Cortizas, Elena M; Zahn, Astrid; Safavi, Shiva et al. (2016) UNG protects B cells from AID-induced telomere loss. J Exp Med 213:2459-2472|