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Elevated Levels of Aneuploidy and Chromosome Rearrangements are Separable Genome Instability Events

ABSTRACT: In Saccharomyces cerevisiae, Elevated Levels of Aneuploidy and Chromosome Rearrangements are Separable Genome Instability Events Controlled by the Tel1 and Mec1 Kinases 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 Saccharomyces cerevisiae proteins Tel1 and Mec1 (homologues of the human ATM and ATR proteins, respectively) are known to participate in the DNA damage response, replication checkpoint, and telomere maintenance pathways and are critical to maintain genome stability. In the absence of induced DNA damage, tel1 mec1 diploid yeast strains exhibit extremely high rates of chromosome aneuploidy. There is a significant bias towards trisomy of chromosomes II, VIII, X, and XII, whereas the smallest chromosomes I and VI are commonly monosomic. tel1 mec1 strains also demonstrate elevated levels of chromosome rearrangements, including translocations as well as interstitial duplications and deletions. Restoring wild-type telomere length with the Cdc13-Est2 fusion protein substantially reduces the amount of chromosome rearrangements in tel1 mec1 strains. This result suggests that most of the rearrangements are initiated by telomere-telomere fusions. However, the telomere defects associated with tel1 mec1 strains do not cause the high rate of aneuploidy, as restoring proper telomere function does not prevent cells from becoming aneuploid. Our data demonstrate that the same mutant genotype can produce both high levels of chromosome rearrangements and high levels of aneuploidy, and these two types of events occur through separate mechanisms.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE17903 | GEO | 2009/09/03

SECONDARY ACCESSION(S): PRJNA119971

REPOSITORIES: GEO

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Project description:In Saccharomyces cerevisiae, a single double-strand break (DSB) triggers extensive phosphorylation of histone H2A (known as gammaH2AX) over 50 kb on either side of the DSB. This modification is carried out by either of yeastM-^Rs checkpoint kinases, the ATM homolog, Tel1, or the ATR homolog, Mec1. In G1-arrested cells, where there is very little 5M-^R to 3M-^R processing of DSB ends, only Tel1 promotes this modification. We have recently described a second modification gammaH2B - the phosphorylation of the C terminal T129 locus of histone H2B which is also carried out by both Mec1 and Tel1 kinases. To understand in detail how gamma-H2AX and gamma-H2B spread along the chromosome from a DSB we have undertaken a high-density analysis of their occupancy where there is a DSB on three different chromosomes. gamma-H2AX and gamma-H2B modifications are similar, but there is a marked absence of gamma-H2B near telomeres. We find that there is reduced gamma-H2AX and gamma-H2B modification over strongly transcribed regions, even taking into account the reduced histone occupancy of these genes. When transcription of the galactose-regulated genes GAL1, GAL10, GAL7 are turned off by the addition of glucose, gamma-H2AX is restored within 5 min; when these genes are again induced, gamma-H2AX is rapidly lost. Regions more distal to the GAL genes have markedly reduced gamma-H2AX levels that rise rapidly when transcription is repressed, suggesting that transcription acts as a barrier to the propagation of gamma-H2AX away from the DSB. The restoration of gamma-H2AX in transcribed regions can be carried out by either Mec1 or Tel1, even 7 h after break induction, suggesting that Tel1 remains associated with damaged chromosomes for an extended time. In addition, we show that gamma-H2AX can be transferred in trans, to regions unlinked to the DSB that lie in close proximity the DSB. Specifically, if a DSB is generated 14 kb from CEN2, gamma-H2AX is transferred to regions around all the other centromeres, in keeping with observed close proximity of all centromere-adjacent chromosome arms. This transfer can be observed even in the absence of formaldehyde crosslinking of the samples.

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Elevated Levels of Aneuploidy and Chromosome Rearrangements are Separable Genome Instability Events

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