DNA polymerase ϵ links the DNA replication machinery to the S phase checkpoint

Navas, Tony; Zhou, Zheng; Elledge, Stephen J.

doi:10.1016/0092-8674(95)90448-4

Cited by 382 publications

(324 citation statements)

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“…Transcriptional activation of the RNR genes, which are responsible for the rate-limiting step of dNTP and DNA synthesis (Huang and Elledge, 1997), and induction of the MAG1 gene, which encodes a DNA-dealkylating enzyme, are markers of the activation of the DNA replication checkpoint (Zhu and Xiao, 2001). This pathway senses blocks in DNA replication and transmits the signal through Mec1p, Rad53p, and Dun1p, delaying mitotic entry (Weinert et al, 1994;Navas et al, 1995;Paulovich and Hartwell, 1995;Desany et al, 1998). The occurrence of RNR and MAG1 gene activation that we observe after exposure to HP, and the dependence of the cell cycle arrest in treatment initiation before S suggests that activation of the replication checkpoint is among the first events occurring during HP-induced oxidative stress and may be responsible for inactivating forkhead-associated transcription.…”

Section: Discussionmentioning

confidence: 69%

Disruption of Yeast Forkhead-associated Cell Cycle Transcription by Oxidative Stress

Shapira

Segal

Botstein

2004

MBoC

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The effects of oxidative stress on yeast cell cycle depend on the stress-exerting agent. We studied the effects of two oxidative stress agents, hydrogen peroxide (HP) and the superoxide-generating agent menadione (MD). We found that two small coexpressed groups of genes regulated by the Mcm1-Fkh2-Ndd1 transcription regulatory complex are sufficient to account for the difference in the effects of HP and MD on the progress of the cell cycle, namely, G1 arrest with MD and an S phase delay followed by a G2/M arrest with HP. Support for this hypothesis is provided by fkh1fkh2 double mutants, which are affected by MD as we find HP affects wild-type cells. The apparent involvement of a forkhead protein in HP-induced cell cycle arrest, similar to that reported for Caenorhabditis elegans and human, describes a potentially novel stress response pathway in yeast. INTRODUCTIONReactive oxygen species (ROS) are by-products of aerobic metabolism, but are also attributes of the extracellular environment. They pose a threat to organisms by damaging a variety of cellular macromolecules, including DNA, membrane lipids, and proteins and are implicated with carcinogenesis, aging, and numerous degenerative diseases (Finkel and Holbrook, 2000;Neumann et al., 2003). The major ROS derived from oxygen are superoxide ions, hydrogen peroxide (HP), and hydroxy radicals, ordered here by increasing reactivity (reviewed in Shackelford et al., 2000).Oxidative stress in yeast has been studied by exposing cells to agents that are already reactive, typically HP, or drugs that cause the intracellular accumulation of reactive oxygen species (Godon et al., 1998;Dumond et al., 2000;Gasch et al., 2000). Menadione (MD) is such a drug, generating reactive superoxide ions, which can be further oxidized to give HP (Monks et al., 1992;Shackelford et al., 2000). It has been previously reported that exposure to HP or MD results in a cell cycle arrest (Flattery-O'Brien and Dawes, 1998;Leroy et al., 2001). However, the arrest points are not similar for the two agents. MD was reported to arrest cells at the G1 phase of the cell cycle, whereas HP was suggested to cause a G2 arrest by an alternate mechanism from that affected by MD (Flattery-O'Brien and Dawes, 1998); others reported that HP exposure causes a delay in the S phase (Leroy et al., 2001).Hundreds of genes are regulated so that they are expressed at specific times in the cell cycle and not at others (Cho et al., 1998;Spellman et al., 1998). The major part of this coordination is achieved by the sequential activation of a small number of transcription regulators (reviewed in Mendenhall and Hodge, 1998): MBF (a complex of Mbp1p and Swi6p) and SBF (a complex of Swi4p and Swi6p) are responsible for activating G1 transcription (Koch et al., 1993); Fkh1p and a complex formed by the cooperative promoter binding of Mcm1p and Fkh2p and a later recruitment of Ndd1p are responsible for activating G2/M transcription (Koranda et al., 2000;Kumar et al., 2000;Pic et al., 2000;Hollenhorst et al., 2001); Swi5p and Ace2p...

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Section: Discussionmentioning

confidence: 69%

Disruption of Yeast Forkhead-associated Cell Cycle Transcription by Oxidative Stress

Shapira

Segal

Botstein

2004

MBoC

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“…Second, unlike the 9-1-1 mutants, rad-5 mutants appear to also be defective in the S-phase replication checkpoint, similar to what is known for the yeast DNA polymerase epsilon. 50 Third, rad-5 mutants do not show Figure 3 Exogenous DNA damage or damage in the form of meiotic recombination intermediates or mitotic replication defects is sensed by numerous proteins. HUS-1 and MRT-2, as part of a trimeric complex, and RAD-5 are involved in this process to allow for the action of the repair machinery.…”

Section: Rad-5/clk-2 Functions In Parallel To the Hus-1/ Mrt-2 Complexmentioning

confidence: 99%

Death and more: DNA damage response pathways in the nematode C. elegans

2003

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Genotoxic stress is a threat to our cells' genome integrity. Failure to repair DNA lesions properly after the induction of cell proliferation arrest can lead to mutations or large-scale genomic instability. Because such changes may have tumorigenic potential, damaged cells are often eliminated via apoptosis. Loss of this apoptotic response is actually one of the hallmarks of cancer. Towards the effort to elucidate the DNA damage-induced signaling steps leading to these biological events, an easily accessible model system is required, where the acquired knowledge can reveal the mechanisms underlying more complex organisms. Accumulating evidence coming from studies in Caenorhabditis elegans point to its usefulness as such. In the worm's germline, DNA damage can induce both cell cycle arrest and apoptosis, two responses that are spatially separated. The latter is a tightly controlled process that is genetically indistinguishable from developmental programmed cell death. Upstream of the central death machinery, components of the DNA damage signaling cascade lie and act either as sensors of the lesion or as transducers of the initial signal detected. This review summarizes the findings of several studies that specify the elements of the DNA damage-induced responses, as components of the cell cycle control machinery, the repairing process or the apoptotic outcome. The validity of C. elegans as a tool to further dissect the complex signaling network of these responses and the high potential for it to reveal important links to cancer and other genetic abnormalities are addressed.

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“…The role of DNA polymerase ε was revealed by mutations that effect the carboxyl terminus of the protein [78]. This region contains a zinc-finger motif dispensable for catalytic activity that may play a role in subunit interactions.…”

Section: The S Cerevisiae S/m Replication Checkpointmentioning

confidence: 99%