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Checking that replication breakdown is not terminal.

Antony M Carr
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Abstract

Two new studies help to clarify the relationship between checkpoint proteins, recombination, and replication fork integrity.

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Ataxia Telangiectasia Mutated ProteinsCell Cycle ProteinsChromosome BreakageDNADNA DamageDNA ReplicationDNA, FungalDNA, Single-StrandedFungal ProteinsIntracellular Signaling Peptides and ProteinsModels, BiologicalProtein Serine-Threonine KinasesRecombination, GeneticRibonucleotide ReductasesS PhaseSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSchizosaccharomycesJournal ArticleComment

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Antony M Carr. 2002-07-26. Checking that replication breakdown is not terminal.. https://doi.org/10.1126/science.1075456

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The ATR kinase phosphorylates both p53 and Chk1 in response to extreme hypoxia (oxygen concentrations of less than 0.02%). In contrast to ATR, loss of ATM does not affect the phosphorylation of these or other targets in response to hypoxia. However, hypoxia within tumors is often transient and is inevitably followed by reoxygenation. We hypothesized that ATR activity is induced under hypoxic conditions because of growth arrest and ATM activity increases in response to the oxidative stress of reoxygenation. Using the comet assay to detect DNA damage, we find that reoxygenation induced significant amounts of DNA damage. Two ATR/ATM targets, p53 serine 15 and histone H2AX, were both phosphorylated in response to hypoxia in an ATR-dependent manner. These phosphorylations were then maintained in response to reoxygenation-induced DNA damage in an ATM-dependent manner. The reoxygenation-induced p53 serine 15 phosphorylation was inhibited by the addition of N-acetyl-l-cysteine (NAC), indicating that free radical-induced DNA damage was mediated by reactive oxygen species. Taken together these data implicate both ATR and ATM as critical roles in the response of hypoxia and reperfusion in solid tumors.

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Protein kinases and their involvement in the cellular responses to genotoxic stress.

Cells are constantly subjected to genotoxic stress, and much has been learned regarding their response to this type of stress during the past year. In general, the cellular genotoxic response can be thought to occur in three stages: (1) damage sensing; (2) activation of signal transduction pathways; (3) biological consequences and attenuation of the response. The biological consequences, in particular, include cell cycle arrest and cell death. Although our understanding of the molecular mechanisms underlying cellular genotoxic stress responses remains incomplete, many cellular components have been identified over the years, including a group of protein kinases that appears to play a major role. Various DNA-damaging agents can activate these protein kinases, triggering a protein phosphorylation cascade that leads to the activation of transcription factors, and altering gene expression. In this review, the involvement of protein kinases, particularly the mitogen-activated protein kinases (MAPKs), at different stages of the genotoxic response is discussed.

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