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• W2018260616 abstract "Purpose/Objective: Exo1p is a member of the Rad2 family of structure-specific nucleases. First isolated as a nuclease activity induced during meiosis in fission yeast, Exo1p has since has been implicated in a multitude of eukaryotic DNA metabolic pathways that include DNA repair, recombination, replication, and telomere integrity. Exo1p involvement in multiple pathways affecting genomic stability makes EXO1 a target for mutation during oncogenesis; supported by the tumor prone phenotype of a mouse model. Exo1p has been best characterized by its role during DNA mismatch repair (MMR). However, recent evidence suggests EXO1 plays a role in the repair or restart of stalled replication forks. Replication checkpoints are cellular failsafe mechanisms that arrest cells and allow for the repair and/or recovery from lesions that prevent faithful duplication of the genome. Replication forks stall when they encounter upstream lesions or dNTP pools are low. When checkpoints are compromised, anomalous structures arise at stalled replication forks that may account for the genomic rearrangements taking place at fragile sites and for the genomic instability of cancer cells. Human cancers invariably have defects in checkpoint proteins, e.g., p53, ATM, BRCA1, Nbs1, Chk2, BLM, & WRN. We examined the role of EXO1 in tolerance of fork stalling lesions and the MMR dependency of this function.Materials/Methods: Isogenic mutant strains of the yeast, S. cerevisiae, were examined using previously defined DNA damage sensitivity assays, mutation rate assays and the yeast two-hybrid assay.Results: Methyl methane sulfonate (MMS) alkylates DNA and at the concentrations used here slows S-phase and stalls replication forks eliciting the replication checkpoint. Sensitivity to MMS is therefore thought to represent inability to deal with these replication stalling lesions. We show decreased survival of the exo1-null strain, suggesting a role for Exo1p in either the repair or accommodation of lesions that stall replication forks. The REV3 gene product is a DNA polymerase that can replicate past fork stalling lesions at the cost of mutation, so-called mutational translesion DNA synthesis. The rev3-null exo1-null mutant shows increased sensitivity suggesting that REV3 and EXO1 act in a redundant fashion to cope with MMS lesions that stall the replication fork. Furthermore, we show this appears to be a MMR-independent role of EXO1.Examining the spontaneous mutation rates of various single and double mutant strains suggests that EXO1 may deal with these fork stalling lesions in an error-free manner. Again, this process is independent of MMR as no interaction was seen with the prototypical MMR gene MLH1.Exo1p interacts with MMR components via sequence specific motifs. Interaction of Exo1p with a MMR complex is thought to be required for MMR. We show that a specific mutation in Exo1p abrogates interaction with Mlh1p using the yeast two-hybrid interaction assay. Next, using an in vivo MMR assay and a specific MLH1 background we see that this EXO1 mutation causes a defect in MMR, but not the DNA damage tolerance pathway as described above. Stated in another fashion, this EXO1 mutation appears to genetically separate Exo1p functions in two separate DNA metabolic pathways; MMR and a MMR-independent DNA damage tolerance pathway.Conclusions: 1EXO1 functions in a pathway that serves to cope with lesions that stall the replication fork.2This EXO1 DNA damage tolerance pathway is separate from its role in MMR and we can genetically separate these functions.3Exo1p interaction with Mlh1p is necessary for efficient MMR despite interaction with the MMR complex via Msh2p. Purpose/Objective: Exo1p is a member of the Rad2 family of structure-specific nucleases. First isolated as a nuclease activity induced during meiosis in fission yeast, Exo1p has since has been implicated in a multitude of eukaryotic DNA metabolic pathways that include DNA repair, recombination, replication, and telomere integrity. Exo1p involvement in multiple pathways affecting genomic stability makes EXO1 a target for mutation during oncogenesis; supported by the tumor prone phenotype of a mouse model. Exo1p has been best characterized by its role during DNA mismatch repair (MMR). However, recent evidence suggests EXO1 plays a role in the repair or restart of stalled replication forks. Replication checkpoints are cellular failsafe mechanisms that arrest cells and allow for the repair and/or recovery from lesions that prevent faithful duplication of the genome. Replication forks stall when they encounter upstream lesions or dNTP pools are low. When checkpoints are compromised, anomalous structures arise at stalled replication forks that may account for the genomic rearrangements taking place at fragile sites and for the genomic instability of cancer cells. Human cancers invariably have defects in checkpoint proteins, e.g., p53, ATM, BRCA1, Nbs1, Chk2, BLM, & WRN. We examined the role of EXO1 in tolerance of fork stalling lesions and the MMR dependency of this function. Materials/Methods: Isogenic mutant strains of the yeast, S. cerevisiae, were examined using previously defined DNA damage sensitivity assays, mutation rate assays and the yeast two-hybrid assay. Results: Methyl methane sulfonate (MMS) alkylates DNA and at the concentrations used here slows S-phase and stalls replication forks eliciting the replication checkpoint. Sensitivity to MMS is therefore thought to represent inability to deal with these replication stalling lesions. We show decreased survival of the exo1-null strain, suggesting a role for Exo1p in either the repair or accommodation of lesions that stall replication forks. The REV3 gene product is a DNA polymerase that can replicate past fork stalling lesions at the cost of mutation, so-called mutational translesion DNA synthesis. The rev3-null exo1-null mutant shows increased sensitivity suggesting that REV3 and EXO1 act in a redundant fashion to cope with MMS lesions that stall the replication fork. Furthermore, we show this appears to be a MMR-independent role of EXO1. Examining the spontaneous mutation rates of various single and double mutant strains suggests that EXO1 may deal with these fork stalling lesions in an error-free manner. Again, this process is independent of MMR as no interaction was seen with the prototypical MMR gene MLH1. Exo1p interacts with MMR components via sequence specific motifs. Interaction of Exo1p with a MMR complex is thought to be required for MMR. We show that a specific mutation in Exo1p abrogates interaction with Mlh1p using the yeast two-hybrid interaction assay. Next, using an in vivo MMR assay and a specific MLH1 background we see that this EXO1 mutation causes a defect in MMR, but not the DNA damage tolerance pathway as described above. Stated in another fashion, this EXO1 mutation appears to genetically separate Exo1p functions in two separate DNA metabolic pathways; MMR and a MMR-independent DNA damage tolerance pathway. Conclusions: 1EXO1 functions in a pathway that serves to cope with lesions that stall the replication fork.2This EXO1 DNA damage tolerance pathway is separate from its role in MMR and we can genetically separate these functions.3Exo1p interaction with Mlh1p is necessary for efficient MMR despite interaction with the MMR complex via Msh2p." @default.
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• W2018260616 date "2005-10-01" @default.
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• W2018260616 title "A Mutation in EXO1 Defines Separable Roles in DNA Mismatch Repair and a DNA Mismatch Repair-independent DNA Damage Tolerance Pathway" @default.
• W2018260616 doi "https://doi.org/10.1016/j.ijrobp.2005.07.245" @default.
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