F. Nina Papavasiliou
The Targeting of the Hypermutation Machinery of Immunoglobulin Genes
Typically, mutations are thought of as disastrous events which, if unchecked, lead to malignant transformation. Yet for at least one process in the body, high levels of mutagenesis are crucial. This process, called somatic hypermutation, takes place in B lymphocytes when they encounter antigen, and leads to the introduction of mutations in the genes of the B cell receptors which bind the antigen. Some of the mutant receptors thus acquired a higher affinity for the antigen, and the cells that harbor such mutant receptors are selected for survival. In this way, select B lymphocytes dramatically increase their affinity for a particular antigen, and along with that, are thought to acquire a long term memory for it. Without hypermutation individuals may become immunocompromised in their ability to deal with antigens. In contrast, unregulated hypermutation leads to malignant transformation.
Little is known about the mechanism of somatic hypermutation, so the central objective of our research is to understand how it works at the molecular level. There are certain molecular features that are associated with the process. In particular, the targeting of the machinery to the immunoglobulin locus is dependent upon the presence of the immunoglobulin enhancers, and we are interested in identifying the factors which bind the enhancer and target the machinery to the locus Once such factors are identified we might begin to understand how hypermutation is sometimes mis-targeted to the wrong loci, and why such mis-targeting might generate lymphomas.