Somatic hypermutation, transcription, and DNA mismatch repair

The data presented in these four recent papers in Immunity (1xBertocci, B., Quint, L., Delbos, F., Garcia, C., Reynaud, C.A., and Weill, J.C. Immunity. 1998; 9: 257–265Abstract | Full Text | Full Text PDF | PubMedSee all References, 4xFrey, S., Bertocci, B., Delbos, F., Quint, L., Weill, J.-C., and Reynaud, C.-A. Immunity. 1998; 9: 127–134Abstract | Full Text | Full Text PDF | PubMed | Scopus (121)See all References, 5xFukita, Y., Jacobs, H., and Rajewsky, K. Immunity. 1998; 9: 105–114Abstract | Full Text | Full Text PDF | PubMed | Scopus (200)See all References, 19xRada, C., Ehrenstein, M.R., Neuberger, M.S., and Milstein, C. Immunity. 1998; 9: 135–141Abstract | Full Text | Full Text PDF | PubMed | Scopus (287)See all References) implicate transcription or accessibility in V-region hypermutation and suggest that MMR plays a role in secondary events that repair or suppress certain types of mutations resulting from the primary process of hypermutation, and thus alters the spectrum of mutations observed in normal cells. Secondary modulations actually appear to be different in MSH2 and PMS2-deficient mice, as indicated by the presence of distinct patterns of mutation. Since the proteins involved in MMR function as complexes, it will be interesting to analyze the mutation spectra of mice that are deficient in MSH3 and/or MSH6, the partners of MSH2 in mitotic MMR (Figure 1Figure 1).Based on the data presented in these recent Immunity papers (1xBertocci, B., Quint, L., Delbos, F., Garcia, C., Reynaud, C.A., and Weill, J.C. Immunity. 1998; 9: 257–265Abstract | Full Text | Full Text PDF | PubMedSee all References, 4xFrey, S., Bertocci, B., Delbos, F., Quint, L., Weill, J.-C., and Reynaud, C.-A. Immunity. 1998; 9: 127–134Abstract | Full Text | Full Text PDF | PubMed | Scopus (121)See all References, 5xFukita, Y., Jacobs, H., and Rajewsky, K. Immunity. 1998; 9: 105–114Abstract | Full Text | Full Text PDF | PubMed | Scopus (200)See all References, 19xRada, C., Ehrenstein, M.R., Neuberger, M.S., and Milstein, C. Immunity. 1998; 9: 135–141Abstract | Full Text | Full Text PDF | PubMed | Scopus (287)See all References), one could envision the model shown in Figure 1Figure 1: (1) The chromatin structure of the transcribed but nonmutating Ig genes is altered/opened as the result of some process of chromatin metabolism (Wade et al. 1997xWade, P.A., Pruss, D., and Wolffe, A.P. Trends Biochem. Sci. 1997; 22: 128–132Abstract | Full Text PDF | PubMed | Scopus (357)See all ReferencesWade et al. 1997). (2) This makes DNA accessible to a DNA mutator factor/complex that introduces mutated nucleotides (16xNeuberger, M.S., Ehrenstein, M.R., Klix, N., Jolly, C.J., Yelamos, J., Rada, C., and Milstein, C. Immunol. Rev. 1998; 162: 107–116Crossref | PubMed | Scopus (96)See all References, 23xStorb, U., Peters, A., Klotz, E., Kim, N., Shen, H.M., Hackett, J., Rogerson, B., and Martin, T.E. Immunol. Rev. 1998; 162: 153–160Crossref | PubMed | Scopus (47)See all References). (3) Some of these mismatched bases are recognized by MMR and repaired. There might be a preference for the repair of certain mismatches (e.g., G/Cs at hot spots) while others are less efficiently repaired. Also, if there is an abundance of mutations, MMR may not be able to repair all of them, leaving some mutations unrepaired. It is still unclear whether transcription is required for mutation or is a manifestation of accessibility (Sleckman et al. 1996xSleckman, B.P., Gorman, J.R., and Alt, F.W. Annu. Rev. Immunol. 1996; 14: 459–481Crossref | PubMed | Scopus (244)See all ReferencesSleckman et al. 1996). If in fact both strands of DNA are subject to the primary mutational event, it is less likely that transcription per se is involved. It is possible that accessibility or transcription factors allow the recruitment of complexes that lead to the primary mutational event. These considerations are still speculative and additional experimentation, using larger numbers of transgenic and genetically defective mice and some of the newer in vitro systems (reviewed by Green et al. 1998xGreen, N.S., Lin, M.M., and Scharff, M.D. Immunol. Rev. 1998; 162: 77–87Crossref | PubMed | Scopus (14)See all ReferencesGreen et al. 1998), will be required to resolve the differences in results in the existing studies. Nevertheless, the studies with mice defective in MMR have alerted us to the possibility that we may not yet know the characteristics of the products of the primary mutational event. They remind us that in order to identify the biochemical mechanisms, the challenge will be to uncouple the primary mutational events from subsequent repair and to identify the components of the protein complexes that are responsible for these processes.*To whom correspondence should be addressed.