ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage

Barzilai, Ari; Rotman, Galit; Shiloh, Yosef

doi:10.1016/s1568-7864(01)00007-6

Cited by 343 publications

(259 citation statements)

References 176 publications

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“…A-T patients suffer from significant neurodegeneration associated with cerebellar ataxia in addition to immunodeficiency, premature ageing, acute radiosensitivity, and cancer predisposition (for review, see Shiloh, 2001). It has been suggested that many of the A-T features might result from elevated levels of oxidative stress in A-T cells or tissues (for review, see Barzilai et al, 2002). Our data suggest that one possible mechanism by which the ATM checkpoint kinase may function to coordinate the cellular response to oxidative stress in mammalian cells is through modulating the transcription of CESR genes.…”

Section: Eukaryotic Ir-response Genesmentioning

confidence: 99%

Global Gene Expression Responses of Fission Yeast to Ionizing Radiation

Watson

Mata

Bähler

et al. 2004

MBoC

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A coordinated transcriptional response to DNA-damaging agents is required to maintain genome stability. We have examined the global gene expression responses of the fission yeast Schizosaccharomyces pombe to ionizing radiation (IR) by using DNA microarrays. We identified ϳ200 genes whose transcript levels were significantly altered at least twofold in response to 500 Gy of gamma IR in a temporally defined manner. The majority of induced genes were core environmental stress response genes, whereas the remaining genes define a transcriptional response to DNA damage in fission yeast. Surprisingly, few DNA repair and checkpoint genes were transcriptionally modulated in response to IR. We define a role for the stress-activated mitogen-activated protein kinase Sty1/Spc1 and the DNA damage checkpoint kinase Rad3 in regulating core environmental stress response genes and IR-specific response genes, both independently and in concert. These findings suggest a complex network of regulatory pathways coordinate gene expression responses to IR in eukaryotes. INTRODUCTIONExposure of cells to DNA-damaging agents such as ionizing radiation (IR) poses a significant threat to genome stability. Cells have therefore evolved complex response mechanisms to maintain genetic integrity after DNA damage. These include cell cycle delay, repair of DNA damage, transcriptional responses, and programmed cell death. Because disruption of any one of these DNA damage responses can lead to genomic instability and cancer, a comprehensive understanding of the individual components and their regulation is crucial.It is well established that many physiological responses to DNA damage are regulated at the level of gene expression. In Escherichia coli, the SOS response induces the expression of a network of genes after DNA damage through the regulatory LexA and RecA proteins (Friedberg et al., 1995). In lower eukaryotes, studies with the budding yeast Saccharomyces cerevisiae have identified a large number of damageinduced genes, including many involved in DNA metabolism and DNA repair (Aboussekhra et al., 1996;Gasch et al., 2001). In the distantly related fission yeast Schizosaccharomyces pombe, rhp51 ϩ , uvi15 ϩ , uvi31 ϩ , UVDE ϩ , and rhp16 ϩ have been shown to be DNA damage inducible (Bang et al., 1996;Davey et al., 1997;Shim et al., 2000).DNA damage checkpoint pathways function to delay the eukaryotic cell cycle in response to DNA damage, thus providing an opportunity for DNA repair. Central to the DNA damage checkpoint pathway are two highly conserved phosphoinositol-related kinases, Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) and their yeast homologs SpTel1 and SpRad3 in S. pombe, and ScTel1 and ScMec1 in S. cerevisiae. Activation of ATM and ATR kinases by DNA damage leads to cell cycle arrest through a number of downstream effector molecules including the effector kinases CHK1/SpChk1/ScChk1 and CHK2/SpCds1/ ScRad53 (for review, see Nyberg et al., 2002). In addition to regulating the cell cycle, DNA damage checkpoints also...

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Section: Eukaryotic Ir-response Genesmentioning

confidence: 99%

Global Gene Expression Responses of Fission Yeast to Ionizing Radiation

Watson

Mata

Bähler

et al. 2004

MBoC

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“…Like DNA-PKcs, ATM is a member of the phosphoinositide 3-kinase-like kinase family. ATM plays a critical role in the early detection of IR-induced DSBs (Barzilai et al, 2002) and is responsible for phosphorylation of numerous proteins involved in cellcycle control, apoptosis and DNA repair (Lavin and Kozlov, 2007).…”

Section: Introductionmentioning

confidence: 99%

DNA-PKcs and ATM influence generation of ionizing radiation-induced bystander signals

et al. 2008

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The phenomenon by which irradiated cells influence nonirradiated neighboring cells, referred to as the bystander effect (BSE), is not well understood in terms of the underlying pathways involved. We sought to enlighten connections between DNA damage repair and the BSE. Utilizing sister chromatid exchange (SCE) frequencies as a marker of the BSE, we performed cell transfer strategies that enabled us to distinguish between generation versus reception of a bystander signal. We find that DNAdependent Protein Kinase catalytic subunit (DNA-PKcs) and Ataxia Telangectasia Mutated (ATM) are necessary for the generation of such a bystander signal in normal human cells following gamma (c)-ray exposure, but are not required for its reception. Importantly, we also show that directly irradiated human cells do not respond to receipt of a bystander signal, helping to explain why the BSE is a low-dose phenomenon. These studies provide the first evidence for a role of the DNA damage response proteins DNA-PKcs and ATM specifically in the generation of a bystander signal and intercellular signaling.

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“…Human diseases that link DNA repair to cancer include: mismatch repair (MMR) associated with colon cancer; human patients with mutations in MUTYH and mice that have both Mutyh and Ogg1 deleted are predisposed to colorectal cancer (David et al, 2007); DNA double strand break (DSB) repair with lymphomas in ataxia telangiectasia (AT) and related disorders (Barzilai et al, 2002); NER with skin cancer in XP (Cleaver and Mitchell, 2005); homologous recombination with breast cancer through the familial breast cancer genes BRCA1 and Fanconi anemia (FANCD1/BRCA2) genes (McKinnon and Caldecott, 2007); crosslink repair with leukemia in Fanconi anemia (FANC) genes (McKinnon and Caldecott, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…The question remains whether mitochondrial ROS themselves, or longer-lived products such as oxidized proteins, lipids, sugars and nitroso compounds migrate sufficiently to reach the nuclear DNA. ROS include an exceedingly complex spectrum of products, many at low concentrations in many different classes of macromolecules (Barzilai et al, 2002). ROS generate many singly modified bases such as 7,8-dihydro-8-oxoguanine (8-oxo-G) that are substrates for base excision repair (BER) (David et al, 2007), and oxidized purine products (5′,8-purine cyclodeoxynucleosides) that require NER for their repair and block transcription (Brooks et al, 2000;Kuraoka et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

Cleaver

Revet

2008

Mechanisms of Ageing and Development

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Cancer, aging, and neurodegeneration are all associated with DNA damage and repair in complex fashions. Aging appears to be a cell and tissue-wide process linked to the insulin-dependent pathway in several DNA repair deficient disorders, especially in mice. Cancer and neurodegeneration appear to have complementary relationships to DNA damage and repair. Cancer arises from surviving cells, or even stem cells, that have down-regulated many pathways, including apoptosis, that regulate genomic stability in a multi-step process. Neurodegeneration however occurs in nondividing neurones in which the persistence of apoptosis in response to reactive oxygen species is, itself, pathological. Questions that remain open concern: sources and chemical nature of naturally occurring DNA damaging agents, especially whether mitochondria are the true source; the target tissues for DNA damage and repair; do the human DNA repair deficient diseases delineate specific pathways of DNA damage relevant to clinical outcomes; if naturally occurring reactive oxygen species are pathological in human repair deficient disease, would anti-oxidants or anti-apoptotic agents be feasible therapeutic agent?

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ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage

Cited by 343 publications

References 176 publications

Global Gene Expression Responses of Fission Yeast to Ionizing Radiation

Global Gene Expression Responses of Fission Yeast to Ionizing Radiation

DNA-PKcs and ATM influence generation of ionizing radiation-induced bystander signals

Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

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