In vertebrates, the process of immunoglobulin (Ig) diversification via VDJ recombination leads to the generation of a vast repertoire of B lymphocytes that are reactive to a wide variety of pathogens. Upon recognition of their cognate antigen, the reactive B cells undergo clonal expansion within organs such as the spleen and lymph nodes forming germinal centers. At the same time, the Ig genes of activated B cells undergo deliberate damage by the enzyme activation-induced deaminase (AID) that converts cytosines to uracils with the purpose to “adapt” the antibody response to the antigen to be defeated. In cells other than the B cells, U:G mismatches are faithfully repaired but in mouse and human B cells the AID-induced lesions are processed by error-prone repair mechanisms. As a consequence, mutations accumulate leading to antibody affinity maturation via somatic hypermutation (SHM) and deletional events of recombination can occur resulting in the Ig isotype switch via class switch recombination (CSR). The mechanisms responsible for the shift from error-free towards error-prone mechanisms of DNA repair at the Ig genes are not yet completely understood. In this thesis, the effects of attenuated DNA damage responses via Checkpoint kinase 1 and the role of the cell cycle during secondary Ig diversification have been investigated.
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