We use the yeast Saccharomyces cerevisae to
study three topics: regulation of genome stability,
telomere length control, and meiotic recombination.
Cancer cells have elevated levels of chromosome aberrations.
We recently showed that yeast strains with mutations
in TEL1 and MEC1 (genes related to
the human gene [ATM] mutated in patients with
ataxia telangiectasia) have very high levels of chromosome
aberrations; these aberrations include translocations
and formation of circular chromosomes. In addition,
the tel1mec1 mutant strains have very
short telomeres, and their chromosomes undergo frequent
telomere-telomere fusions
When human cells are treated with drugs that inhibit
DNA replication, the chromosome break at specific
sites, termed “fragile sites”. To see
whether similar sites were present in yeast, we constructed
strains in which the level of DNA polymerase was
regulated by the amount of galactose in the medium.
We showed that strains with low levels of DNA polymerase
had very high rates of chromosome rearrangements.
One site on chromosome III (which we termed FS2)
was a hotspot for these rearrangements. We showed
that FS2 had an inverted pair of Ty elements and
that low levels of DNA polymerase resulted in a discrete
break at FS2. The broken end was usually repaired
by homologous recombination with other Ty elements
in the genome.
The rate of meiotic recombination varies dramatically
at different positions in the genome. We found that
recombination hotspots (regions of elevated recombination)
require the binding of transcription factors. We developed
methods of analyzing hotspots using DNA microarrays.
This analysis suggests that hotspots may represent
regions of hyper-modified histones. Meiotic recombination
is suppressed near the telomeres and centromeres of
the yeast chromosome. We are currently using microarrays
to examine this suppression in strains with mutations
affecting chromatin modifications and/or chromosome
structure.
