MECHANISMS OF GENOME INSTABILITY

基因组的稳定性，特别是人类，受到以下因素的影响

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 abundant in the genome. Previously we had demonstrated that long inverted repeats could stimulate DNA deletions and homologous recombination. Various forms of recombination stimulated by inverted repeats are associated with chromosomal rearrangements (deletions and translocations). We have demonstrated that long inverted repeats create a strong hotspot for interchromosomal recombination and translocations induced by environmental genotoxicants. This is the first demonstration of a hotspot for induced recombination driven by organization of a DNA sequence. The information about induced hotspot and about structural parameters facilitating inverted repeat stimulated recombination are being in conjunction with the Human Genome database to find potential hotspots of environmentally induced changes. The study of deletions has been extended to investigations of novel mechanisms of genomic rearrangements associated with random short DNA repeats and homonucleotide runs. The mismatch repair system is known to be involved in various aspects of genomic stability including genetic control of predisposition to cancer, manifesting in the instability of simple repeats. We have found that mutations that arise in short homonucleotide runs as a result of a RAD52 mutator mutation are not prevented by the mismatch repair system. These results suggest existence of genetic backgrounds other than mismatch repair deficiency that are highly susceptible to mutation production.