Recombination is required for the repair of many types of lesions and it can be a source of genetic diversity. DNA sequence divergence (homoeology) is expected to impede recombination efficiency because of constraints inherent in the biochemical reactions. Ancillary genetic factors such as DNA-mismatch repair are also expected to affect recombination between homologous DNAs. We are examining the requirements and consequences of recombination between divergent DNAs to gain insight on mechanisms of recombination, mechanisms of chromosome rearrangements, and possibly mechanisms of initiation of carcinogenesis. We have previously demonstrated that recombinational repair in plasmid DNA occurs less efficiently if the chromosomal DNA available as the template for repair is homeologous rather than homologous. Proficiency for DNA mismatch repair appears to have little or no effect on the frequency or products (examined at the molecular level) of these recombination events. Based on these results, we suggest updated versions of models for recombinational repair. We are extending this analysis to defects in other DNA repair functions. To further elaborate the effect of mismatch repair on recombination between diverged DNAs, we have studied model heteroduplex plasmids which resemble structures proposed as intermediates in recombination between diverged DNAs. We previously demonstrated that a mixture of closely related heteroduplex plasmids survive transformation at nearly the same rate in methyl-directed mismatch repair (MMR)-proficient or deficient E. coli. We are developing methods of producing subfractions of model heteroduplex plasmids to study the effects of specific configurations on susceptibility to attack by MMR; the exact configuration is an important parameter in models of recombination repair. These experiments are currently being extended to S. cerevisiae.
| Lobachev, Kirill S; Gordenin, Dmitry A; Resnick, Michael A (2002) The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements. Cell 108:183-93 |
| Stenger, J E; Lobachev, K S; Gordenin, D et al. (2001) Biased distribution of inverted and direct Alus in the human genome: implications for insertion, exclusion, and genome stability. Genome Res 11:12-27 |
| Lobachev, K S; Stenger, J E; Kozyreva, O G et al. (2000) Inverted Alu repeats unstable in yeast are excluded from the human genome. EMBO J 19:3822-30 |
