Genomics

Dataset Information

28

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. Overall design: The strains in this series consist of 23 diploid yeast strains homozygous null for TEL1, MEC1, and SML1 as well as four wild-type controls. The experimental strains were subcultured for approximately 100 generations before introducing a wild-type copy of MEC1 on a plasmid to capture the current complement of chromosomal aberrations and limit further genome instability during the course of analysis. Genomic DNA from each experimental strains was competitively hybridized with genomic DNA from the isogenic reference strain MS71. This experiment allows the determination of alterations to chromosome number and chromosome structure in diploid strains lacking TEL1, MEC1, and SML1 following subculturing.

INSTRUMENT(S): Lieb Lab at UNC-CH_Yeast Whole-genome Array (PCR-based)_for Buck MJ et al.

SUBMITTER: Jennifer Lynn McCulley  

PROVIDER: GSE17903 | GEO | 2009-09-03

SECONDARY ACCESSION(S): PRJNA119971

REPOSITORIES: GEO

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Publications

Chromosome rearrangements and aneuploidy in yeast strains lacking both Tel1p and Mec1p reflect deficiencies in two different mechanisms.

McCulley Jennifer L JL   Petes Thomas D TD  

Proceedings of the National Academy of Sciences of the United States of America 20100607 25


The human ATM and ATR proteins participate in the DNA damage and DNA replication checkpoint pathways and are critical to maintaining genome stability. The Saccharomyces cerevisiae homologs of ATM and ATR are Tel1p and Mec1p, respectively. Haploid tel1 mec1 strains have very short telomeres and very high rates of chromosomal aberrations. Here, we examine genetic stability in tel1 mec1 diploid cells. In the absence of induced DNA damage, these yeast strains had very high frequencies of aneuploidy  ...[more]

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