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<p>Cancer cells often have elevated frequencies of chromosomal aberrations, and it
is likely that loss of genome stability is one driving force behind tumorigenesis.
Deficiencies in DNA replication, DNA repair, or cell cycle checkpoints can all contribute
to increased rates of chromosomal duplications, deletions and translocations. The
human ATM and ATR proteins are known to participate in the DNA damage response and
DNA replication checkpoint pathways and are critical to maintaining genome stability.
The <italic>Saccharomyces cerevisiae</italic> homologues of ATM and ATR are Tel1p
and Mec1p, respectively. Because Tel1p and Mec1p are partially functionally redundant,
loss of both Tel1p and Mec1p in haploid yeast cells (<italic>tel1 mec1</italic> strains)
results in synergistically elevated rates of chromosomal aberrations, including terminal
duplications, chromosomal duplications, and telomere-telomere fusions. To determine
the effect of Tel1p and Mec1p on chromosome aberrations that cannot be recovered in
haploid strains, such as chromosome loss, I investigated the phenotypes associated
with the <italic>tel1 mec1</italic> mutations in diploid cells. In the absence of
induced DNA damage, <italic>tel1 mec1</italic> diploid yeast strains exhibit extremely
high rates of aneuploidy and chromosome rearrangements. There is a significant bias
towards trisomy of chromosomes II, VIII, X, and XII, whereas the smallest chromosomes
I and VI are commonly monosomic. </p>
<p> The telomere defects associated with <italic>tel1 mec1</italic> strains do
not cause the high rates of aneuploidy, as restoring wild-type telomere length in
these strains by expression of the Cdc13p-Est2p fusion protein does not prevent cells
from becoming aneuploid. The <italic>tel1 mec1</italic> diploids are not sensitive
to the microtubule-destabilizing drug benomyl, nor do they arrest the cell cycle in
response to the drug, indicating that the spindle assembly checkpoint is functional.
The chromosome missegregation phenotypes of <italic>tel1 mec1</italic> diploids mimic
those observed in mutant strains that do not achieve biorientation of sister chromatids
during mitosis. </p>
<p> The chromosome rearrangements in <italic>tel1 mec1</italic> cells reflect
both homologous recombination between non-allelic Ty elements, as well as non-homologous
end joining (NHEJ) events. Restoring wild-type telomere length with the Cdc13p-Est2p
fusion protein substantially reduces the levels of chromosome rearrangements (terminal
additions and deletions of chromosome arms, interstitial duplications, and translocations).
This result suggests that most of the rearrangements in <italic>tel1 mec1</italic>
diploids are initiated by telomere-telomere fusions. One common chromosome rearrangement
in <italic>tel1 mec1</italic> strains is an amplification of sequences on chromosome
XII between the left telomere and rDNA sequences on the right arm. I have termed
this aberration a "schromosome." Preliminary evidence indicates that the schromosome
exists in the <italic>tel1 mec1</italic> cells as an uncapped chromosome fragment
that gets resected over time.</p>
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