The stability of genomes, particularly humans, is influenced by opportunities for recombination between long (0.3 -10 kb) repeats of diverged DNAs such as ALUs and LINES and rearrangements between very short (4-10 bp) random repeats. Both types of repeats are very abundant in all parts of the genome, therefore interaction between them must be prevented to avoid chromosomal rearrangements. Previously we had demonstrated that long inverted repeats could stimulate DNA deletions and homologous recombination. This work has been extended to investigations of novel mechanisms of genomic rearrangements associated with both long and short DNA repeats. We have demonstrated a role for DNA replication-- via replication slippage--in rearrangements between distant short, 4-10 bp repeats in yeast. The mismatch repair system is known to be involved in various aspects of genomic stability including genetic control of predisposition to cancer. We have found that under conditions of stressed replication (using a defective DNA polymerase) 1 bp replication slippage errors are efficiently corrected by mismatch repair whereas 30 bp replication slippage errors are insensitive to mismatch repair. These results suggest another cellular system maintaining genome stability during replication. We have also identified that DNA arrangement influences the capacity for recombination. Chromosomal rearrangements associated with long DNA repeats, i.e. ectopic interchromosomal rearrangements, are facilitated when the third repeat is placed nearby in inverted orientation. In addition, inverted repeats greatly enhance rearrangements between 30% diverged repeats, that normally do not undergo recombination. The effects of DNA arrangements on recombination are also influenced by DNA replication.
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