Recombination is required for the repair of many types of lesions and it can be a source of genetic diversity. We are investigating the requirements for homology in recombination and the consequences of recombination between DNA divergent sequences. From this information we can determine the mechanisms of chromosome rearrangements, generation of novel genes and possible mechanisms of initiation in carcinogenesis. In addition we are developing a system for the genetic detection of double-strand damage after exposure to very low, nonlethal doses of an agent. We developed a method for examining the role of homology between a specific pair of homologues in """"""""protecting"""""""" chromosomes against DNA damage. Nonlethal radiation doses to S. cerevisiae diploid cells containing a single pair of DNA divergent (80% homologous) but functionally homologous chromosomes greatly increased aneuploidy induction (chromosomes III or V from S. cerevisiae and S. carlsbergenesis). Using these approaches, we have investigated the fate of damaged human DNA contained in yeast vectors in yeast (YACs). Provided there is an homologous YAC, repair is efficient but there is little or none in the absence of a homologue. We are investigating the possibility of recombination between repetitive sequences in the human DNA. We have concluded that recombinational repair can occur between sequences of limited homology. This was also demonstrated by radiation induced intragenic recombination between homoeologous chromosomes. We have also shown that gene targeting in yeast can occur with limited homology. Since mismatch repair would be expected to play an important role, we have begun to investigate model heteroduplex transforming molecules in various yeast and E. coli mutants.
| 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 |
