Dataset Information

The Saccharomyces cerevisiae RAD9, RAD17 and RAD24 genes are required for suppression of mutagenic post-replicative repair during chronic DNA damage.

ABSTRACT: In Saccharomyces cerevisiae, a DNA damage checkpoint in the S-phase is responsible for delaying DNA replication in response to genotoxic stress. This pathway is partially regulated by the checkpoint proteins Rad9, Rad17 and Rad24. Here, we describe a novel hypermutable phenotype for rad9Delta, rad17Delta and rad24Delta cells in response to a chronic 0.01% dose of the DNA alkylating agent MMS. We report that this hypermutability results from DNA damage introduction during the S-phase and is dependent on a functional translesion synthesis pathway. In addition, we performed a genetic screen for interactions with rad9Delta that confer sensitivity to 0.01% MMS. We report and quantify 25 genetic interactions with rad9Delta, many of which involve the post-replication repair machinery. From these data, we conclude that defects in S-phase checkpoint regulation lead to increased reliance on mutagenic translesion synthesis, and we describe a novel role for members of the S-phase DNA damage checkpoint in suppressing mutagenic post-replicative repair in response to sublethal MMS treatment.

SUBMITTER: Murakami-Sekimata A

PROVIDER: S-EPMC2893243 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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The Saccharomyces cerevisiae RAD9, RAD17 and RAD24 genes are required for suppression of mutagenic post-replicative repair during chronic DNA damage.

Murakami-Sekimata Akiko A Huang Dongqing D Piening Brian D BD Bangur Chaitanya C Paulovich Amanda G AG

DNA repair 20100515 7

In Saccharomyces cerevisiae, a DNA damage checkpoint in the S-phase is responsible for delaying DNA replication in response to genotoxic stress. This pathway is partially regulated by the checkpoint proteins Rad9, Rad17 and Rad24. Here, we describe a novel hypermutable phenotype for rad9Delta, rad17Delta and rad24Delta cells in response to a chronic 0.01% dose of the DNA alkylating agent MMS. We report that this hypermutability results from DNA damage introduction during the S-phase and is depen ...[more]

PMID: 20472512

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Project description:Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS-related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans.

Dataset Information

The Saccharomyces cerevisiae RAD9, RAD17 and RAD24 genes are required for suppression of mutagenic post-replicative repair during chronic DNA damage.

Publications

The Saccharomyces cerevisiae RAD9, RAD17 and RAD24 genes are required for suppression of mutagenic post-replicative repair during chronic DNA damage.

Similar Datasets

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