Essential
            <i>Saccharomyces cerevisiae</i>
            genome instability suppressing genes identify potential human tumor suppressors

Srivatsan, Anjana; Li, Binzhong; Sanchez, Dafne N.; Somach, Steven B.; Silva, Vandeclécio L. da; Souza, Sandro J. de; Putnam, Christopher D.; Kolodner, Richard D.

doi:10.1073/pnas.1906921116

Cited by 10 publications

(19 citation statements)

References 64 publications

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“…Evaluation of known S. cerevisiae SL interactions ( 21 ) demonstrated that RAD27 had the greatest number of SL relationships with the GIS genes identified in our studies ( 23 – 25 ) (59 SL partners; Fig. 1 A and Dataset S1 ).…”

Section: Resultsmentioning

confidence: 78%

“…which then implicated their corresponding human homologs and pathway genes as candidate human GIS genes (24,25). Analysis of The Cancer Genome Atlas data has suggested that the human GIS genes are frequently defective in cancers that exhibit genome instability (24,25).…”

Section: Significancementioning

confidence: 99%

“…In a previous study, we used SL relationships in S. cerevisiae and other functional genomics datasets to construct a network of genes that were predicted to act in the suppression of genome rearrangements ( 23 , 24 ). Genetic screens based on these network predictions and validation studies identified 266 genome instability-suppressing (GIS) genes and an additional 38 candidate GIS genes, which then implicated their corresponding human homologs and pathway genes as candidate human GIS genes ( 24 , 25 ). Analysis of The Cancer Genome Atlas data has suggested that the human GIS genes are frequently defective in cancers that exhibit genome instability ( 24 , 25 ).…”

mentioning

confidence: 99%

“…Genetic screens based on these network predictions and validation studies identified 266 genome instability-suppressing (GIS) genes and an additional 38 candidate GIS genes, which then implicated their corresponding human homologs and pathway genes as candidate human GIS genes ( 24 , 25 ). Analysis of The Cancer Genome Atlas data has suggested that the human GIS genes are frequently defective in cancers that exhibit genome instability ( 24 , 25 ). In the present study, we have performed experiments to determine if S. cerevisiae SL networks can predict possible therapeutic targets for cancers with defects in GIS genes, initially focusing on cancers with HR defects caused by BRCA1 and BRCA2 defects, thereby identifying the nuclease Rad27/FEN1 as an attractive candidate therapeutic target.…”

mentioning

confidence: 99%

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FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination

Guo

Ishii

Mueller

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic lethality strategies for cancer therapy exploit cancer-specific genetic defects to identify targets that are uniquely essential to the survival of tumor cells. Here we show RAD27/FEN1, which encodes flap endonuclease 1 (FEN1), a structure-specific nuclease with roles in DNA replication and repair, and has the greatest number of synthetic lethal interactions with Saccharomyces cerevisiae genome instability genes, is a druggable target for an inhibitor-based approach to kill cancers with defects in homologous recombination (HR). The vulnerability of cancers with HR defects to FEN1 loss was validated by studies showing that small-molecule FEN1 inhibitors and FEN1 small interfering RNAs (siRNAs) selectively killed BRCA1- and BRCA2-defective human cell lines. Furthermore, the differential sensitivity to FEN1 inhibition was recapitulated in mice, where a small-molecule FEN1 inhibitor reduced the growth of tumors established from drug-sensitive but not drug-resistant cancer cell lines. FEN1 inhibition induced a DNA damage response in both sensitive and resistant cell lines; however, sensitive cell lines were unable to recover and replicate DNA even when the inhibitor was removed. Although FEN1 inhibition activated caspase to higher levels in sensitive cells, this apoptotic response occurred in p53-defective cells and cell killing was not blocked by a pan-caspase inhibitor. These results suggest that FEN1 inhibitors have the potential for therapeutically targeting HR-defective cancers such as those resulting from BRCA1 and BRCA2 mutations, and other genetic defects.

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Section: Resultsmentioning

confidence: 78%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination

Guo

Ishii

Mueller

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…This theory is consistent with the recent suggestion that POLE defects contribute to non-hypermutagenic tumors 24 . It is noteworthy that the pol2-12 checkpoint defective allele also leads to increased GCR levels 47 . As the pathogenic significance of the majority of non-EXO cancer-associated POLE mutations remains unknown, our work suggests that modeling these mutations in yeast can provide an effective way to distinguish their genomic instability effects between DNA hyperrearrangements versus hyper-mutations.…”

Section: Discussionmentioning

confidence: 99%

DNA polymerase ε relies on a unique domain for efficient replisome assembly and strand synthesis

et al. 2020

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DNA polymerase epsilon (Pol ε) is required for genome duplication and tumor suppression. It supports both replisome assembly and leading strand synthesis; however, the underlying mechanisms remain to be elucidated. Here we report that a conserved domain within the Pol ε catalytic core influences both of these replication steps in budding yeast. Modeling cancerassociated mutations in this domain reveals its unexpected effect on incorporating Pol ε into the four-member pre-loading complex during replisome assembly. In addition, genetic and biochemical data suggest that the examined domain supports Pol ε catalytic activity and symmetric movement of replication forks. Contrary to previously characterized Pol ε cancer variants, the examined mutants cause genome hyper-rearrangement rather than hypermutation. Our work thus suggests a role of the Pol ε catalytic core in replisome formation, a reliance of Pol ε strand synthesis on a unique domain, and a potential tumor-suppressive effect of Pol ε in curbing genome rearrangements .

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Altered S‐AdenosylMethionine availability impacts dNTP pools in Saccharomyces cerevisiae

Panmanee,

Tran,

Seye

et al. 2024

Yeast

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Saccharomyces cerevisiae has long been used as a model organism to study genome instability. The SAM1 and SAM2 genes encode AdoMet synthetases, which generate S‐AdenosylMethionine (AdoMet) from Methionine (Met) and ATP. Previous work from our group has shown that deletions of the SAM1 and SAM2 genes cause changes to AdoMet levels and impact genome instability in opposite manners. AdoMet is a key product of methionine metabolism and the major methyl donor for methylation events of proteins, RNAs, small molecules, and lipids. The methyl cycle is interrelated to the folate cycle which is involved in de novo synthesis of purine and pyrimidine deoxyribonucleotides (dATP, dTTP, dCTP, and dGTP). AdoMet also plays a role in polyamine production, essential for cell growth and used in detoxification of reactive oxygen species (ROS) and maintenance of the redox status in cells. This is also impacted by the methyl cycle's role in production of glutathione, another ROS scavenger and cellular protectant. We show here that sam2∆/sam2∆ cells, previously characterized with lower levels of AdoMet and higher genome instability, have a higher level of each dNTP (except dTTP), contributing to a higher overall dNTP pool level when compared to wildtype. Unchecked, these increased levels can lead to multiple types of DNA damage which could account for the genome instability increases in these cells.

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Essential Saccharomyces cerevisiae genome instability suppressing genes identify potential human tumor suppressors

Cited by 10 publications

References 64 publications

FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination

FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination

DNA polymerase ε relies on a unique domain for efficient replisome assembly and strand synthesis

Altered S‐AdenosylMethionine availability impacts dNTP pools in Saccharomyces cerevisiae

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