Novel Connections Between DNA Replication, Telomere Homeostasis, and the DNA Damage Response Revealed by a Genome-Wide Screen for <i>TEL1/ATM</i> Interactions in <i>Saccharomyces cerevisiae</i>

Piening, Brian D.; Huang, Dongqing; Paulovich, Amanda G.

doi:10.1534/genetics.113.149849

Cited by 8 publications

(8 citation statements)

References 86 publications

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“…We, and others, have uncovered genetic interactions with tel1 Δ in response to DNA-damaging agents. Two previous studies demonstrated that tel1 Δ in combination with mutations affecting 9-1-1 DDR checkpoint genes are more sensitive to CPT, ionizing radiation, and the alkylating agent MMS ( Guenole et al 2013 ; Piening et al 2013 ). Piening and co-workers also identified 10 interactions with tel1 Δ that were specific to treatment with MMS.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Cytotoxicity: Digenic Interactions with TEL1/ATM Mutations Reveal Sensitivity to Low Doses of Camptothecin

O’Neil

Moshgabadi

et al. 2014

Genetics

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Many tumors contain mutations that confer defects in the DNA-damage response and genome stability. DNA-damaging agents are powerful therapeutic tools that can differentially kill cells with an impaired DNA-damage response. The response to DNA damage is complex and composed of a network of coordinated pathways, often with a degree of redundancy. Tumor-specific somatic mutations in DNA-damage response genes could be exploited by inhibiting the function of a second gene product to increase the sensitivity of tumor cells to a sublethal concentration of a DNA-damaging therapeutic agent, resulting in a class of conditional synthetic lethality we call synthetic cytotoxicity. We used the Saccharomyces cerevisiae nonessential gene-deletion collection to screen for synthetic cytotoxic interactions with camptothecin, a topoisomerase I inhibitor, and a null mutation in TEL1, the S. cerevisiae ortholog of the mammalian tumor-suppressor gene, ATM. We found and validated 14 synthetic cytotoxic interactions that define at least five epistasis groups. One class of synthetic cytotoxic interaction was due to telomere defects. We also found that at least one synthetic cytotoxic interaction was conserved in Caenorhabditis elegans. We have demonstrated that synthetic cytotoxicity could be a useful strategy for expanding the sensitivity of certain tumors to DNA-damaging therapeutics.

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Section: Discussionmentioning

confidence: 99%

Synthetic Cytotoxicity: Digenic Interactions with TEL1/ATM Mutations Reveal Sensitivity to Low Doses of Camptothecin

O’Neil

Moshgabadi

et al. 2014

Genetics

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“…These included Yku70, members of the 9-1-1 pathway, the CCR4-NOT deadenylase complex, nuclear pore components, and several histone deacetylases. Most of these mutants caused the MMS sensitivity due to their effects on telomeres (Piening et al, 2013).…”

Section: Systems Biology Of Telomere Biologymentioning

confidence: 99%

Biology of telomeres: lessons from budding yeast

Kupiec

2014

FEMS Microbiol Rev

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Telomeres are nucleoprotein structures that cap the ends of the linear eukaryotic chromosomes and thereby protect their stability and integrity. Telomeres play central roles in maintaining the genome's integrity, distinguishing between the natural chromosomal ends and unwanted double-stranded breaks. In addition, telomeres are replicated by a special reverse transcriptase called telomerase, in a complex mechanism that is coordinated with the genome's replication. Telomeres also play an important role in tethering the chromosomes to the nuclear envelope, thus helping in positioning the chromosomes within the nucleus. The special chromatin configuration of telomeres affects the expression of nearby genes; nonetheless, telomeres are transcribed, creating noncoding RNA molecules that hybridize to the chromosomal ends and seem to play regulatory roles. The yeast Saccharomyces cerevisiae, with its sophisticated genetics and molecular biology, has provided many fundamental concepts in telomere biology, which were later found to be conserved in all organisms. Here, we present an overview of all the aspects of telomere biology investigated in yeast, which continues to provide new insights into this complex and important subject, which has significant medical implications, especially in the fields of aging and cancer.

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“…The mec1 mutant is considered to be much more sensitive to DNA-damaging agents than the tel1 mutant (Greenwell et al 1995 ; Morrow et al 1995 ). However, under certain conditions (e.g., depletion of dNTP pools through pretreatment with HU), the tel1 cells were found to be methyl methanesulfonate (MMS)-sensitive compared to wild-type cells (Piening et al 2013 ). More recently, it has been reported that Tel1p has two functions in checkpoint response to DSBs (Mantiero et al 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Affected chromosome homeostasis and genomic instability of clonal yeast cultures

et al. 2015

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Yeast cells originating from one single colony are considered genotypically and phenotypically identical. However, taking into account the cellular heterogeneity, it seems also important to monitor cell-to-cell variations within a clone population. In the present study, a comprehensive yeast karyotype screening was conducted using single chromosome comet assay. Chromosome-dependent and mutation-dependent changes in DNA (DNA with breaks or with abnormal replication intermediates) were studied using both single-gene deletion haploid mutants (bub1, bub2, mad1, tel1, rad1 and tor1) and diploid cells lacking one active gene of interest, namely BUB1/bub1, BUB2/bub2, MAD1/mad1, TEL1/tel1, RAD1/rad1 and TOR1/tor1 involved in the control of cell cycle progression, DNA repair and the regulation of longevity. Increased chromosome fragility and replication stress-mediated chromosome abnormalities were correlated with elevated incidence of genomic instability, namely aneuploid events—disomies, monosomies and to a lesser extent trisomies as judged by in situ comparative genomic hybridization (CGH). The tor1 longevity mutant with relatively balanced chromosome homeostasis was found the most genomically stable among analyzed mutants. During clonal yeast culture, spontaneously formed abnormal chromosome structures may stimulate changes in the ploidy state and, in turn, promote genomic heterogeneity. These alterations may be more accented in selected mutated genetic backgrounds, namely in yeast cells deficient in proper cell cycle regulation and DNA repair.

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Novel Connections Between DNA Replication, Telomere Homeostasis, and the DNA Damage Response Revealed by a Genome-Wide Screen for TEL1/ATM Interactions in Saccharomyces cerevisiae

Cited by 8 publications

References 86 publications

Synthetic Cytotoxicity: Digenic Interactions with TEL1/ATM Mutations Reveal Sensitivity to Low Doses of Camptothecin

Synthetic Cytotoxicity: Digenic Interactions with TEL1/ATM Mutations Reveal Sensitivity to Low Doses of Camptothecin

Biology of telomeres: lessons from budding yeast

Affected chromosome homeostasis and genomic instability of clonal yeast cultures

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