Somatic hypermutation is, in part, responsible, for affinity maturation during an immune response. This process is highly regulated at both the cellular as well as at the molecular level. The frequency, distribution and nature of these mutations strongly suggest that the hypermutation process is not random. The underlying mechanism, however, has remained elusive.
Recently, lymphoid-specific enhancers have been shown to play a crucial rule in targetting the antibody V region (Betz et al., Cell 77, 239-248; Sharpe et al., EMBO J. 10, 2139-2145). Moreover, is has been demonstrated that the process exhibits specific base substitution preferences (Betz et al., PNAC, 90, 2385-2388) and is able to distinguish between the coding and noncoding strand. The aim of this project is to gain a better understanding of the regulation of the hypermutation machinery. For example, transgenic mice have been produced in Dr. Neuberger's laboratory to characterize the roles of enhancers. Using the above system I have already obtained interesting results (Nature, submitted). I will continue these studies as a PhD student starting October 1995.
The results will facilitate the establishing of an in vitro hypermutati system which could be used, for example, to produce mutant
non-immunoglobulin proteins in vivo.