The Jackson Laboratory

Over the past few years our lab has shown that the homologous recombination (HR) pathway of DNA double strand break repair has crucial and unexpected functions in B-cell development. In the bone marrow, B-cells develop from a progenitor stage to a fully mature B-cell capable of recognizing antigens after migration to the periphery. During development in the bone marrow, B-cells undergo successive rounds of clonal expansion, associated with rapid cellular proliferation. We have shown that during these phases of rapid proliferation, the homologous recombination factor XRCC2 is essential for B-cell viability and genomic stability. In the absence of XRCC2, collapsed or stalled DNA replication forks fail to restart and B-cells either arrest (probably permanently) or incur extreme genome instability. Unexpectedly, we recently discovered a separate and distinct function of XRCC2 in mature peripheral B-cells after they have been antigen activated. After such activation, B-cells normally initiate two programmed mutational processes: somatic hypermutation, to fine-tune their antigen binding affinity; or antibody class switching, to modify the precise immune function of each specific antibody. These two processes require a specialized enzyme, AID, to alter the DNA sequences at specified locations in the B-cell genome. We have discovered that (1) AID actually functions promiscuously in activated B-cells, attacking numerous locations throughout the genome; and (2) XRCC2 is essential for normal B-cells to resist mutation, chromosome breakage, and B-cell death resulting from promiscuous AID activity. This AID-induced, widespread genomic instability is termed collateral damage (as opposed to targeted damage in the immunoglobulin genes). Our findings refine our understanding of B-cell developments, showing that proper adaptive immunity results from a careful balancing act between too little and too much DNA damage. There are a number of interesting implications of these findings that we are continuing to explore: How is AID targeted to the immunoglobulin genes and mis-targeted to other loci? What genomic substrates are susceptible to AID-induced damage and how to they relate to cancer development? What genes are required for the prevention or repair of collateral damage?