Replication Stress and Chromatin Context Link ATM Activation to a Role in DNA Replication

Olcina, Monica M.; Foskolou, Iosifina P.; Anbalagan, Selvakumar; Senra, Joana; Pires, Isabel; Jiang, Yanyan; Ryan, Anderson J.; Hammond, Ester M.

doi:10.1016/j.molcel.2013.10.019

Cited by 107 publications

(130 citation statements)

References 42 publications

(46 reference statements)

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“…Although there is emerging evidence for a role of ATM in promoting tumorigenesis, early in tumorigenesis, ATM signaling provides a barrier to activated oncogenes and tumor progression, rather than promoting cancer (Bartkova et al, 2005;Gorgoulis et al, 2005;Halazonetis et al, 2008) (see Box 1), and ATM has been one of the prime drug targets for cancer therapy (see Box 2). Under hypoxia, increased replication stress and H3K9me3 levels, together with repressed PP2A activity, facilitate ATM activation and prevent DSB formation, thereby enabling normal replication (Olcina et al, 2013). Activated ATM also phosphorylates and activates the transcriptional regulator hypoxia-inducible factor 1α (HIF1α), resulting in the upregulation of REDD1, a TSC2 activator; this leads to suppression of mTORC1 signaling and results in a decrease of anabolic processes and an increase in catabolic processes (Cam et al, 2010).…”

Section: Box 2 Atr and Atm As Targets For Cancer Therapymentioning

confidence: 99%

ATM and ATR signaling at a glance

Awasthi

Foiani

Kumar

2015

Journal of Cell Science

235

228

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There was an error published in J. Cell Sci. 128, 4255-4262.An incorrect citation and reference was given for the last sentence in Box 2. The correct citation and reference are: A recent review provides a detailed update on ATM and ATR inhibitors, and their potential as drug targets (Weber and Ryan, 2015).Weber, A.M. and Ryan, A.J. (2015). ATM and ATR as therapeutic targets in cancer. Pharmacol Ther. 149, 124-138.The authors apologise to the readers for any confusion that this error might have caused. Although the role of both ATM and ATR in DNA repair, cell cycle regulation and apoptosis have been well studied, both still remain in the focus of current research activities owing to their role in cancer. Recent advances in the field suggest that these proteins have an additional function in maintaining cellular homeostasis under both stressed and non-stressed conditions. In this Cell Science at a Glance article and the accompanying poster, we present an overview of recent advances in ATR and ATM research with emphasis on that into the modes of ATM and ATR activation, the different signaling pathways they participate in -including those that do not involve DNA damage -and highlight their relevance in cancer. 1285

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Section: Box 2 Atr and Atm As Targets For Cancer Therapymentioning

confidence: 99%

ATM and ATR signaling at a glance

Awasthi

Foiani

Kumar

2015

Journal of Cell Science

235

228

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“…Part of the complexity of the DNA damage response derives from the important crosstalk with the replication machinery. Components of the DNA damage response pathway also play roles in replication or replication/transcription coupling, independently of DNA damage induction (Gamper et al, 2012;Olcina et al, 2013;Shechter et al, 2004;Turinetto et al, 2012). Hence, one could argue that the DNA damage response may be altered in Epi cells during this developmental window because of their high proliferation rate.…”

Section: Hypersensitivity To Radiation Correlates With Hyperproliferamentioning

confidence: 99%

Differential DNA damage signalling and apoptotic threshold correlate with mouse epiblast-specific hypersensitivity to radiation

Laurent

Blasi

2015

Development

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Between implantation and gastrulation, mouse pluripotent epiblast cells expand enormously in number and exhibit a remarkable hypersensitivity to DNA damage. Upon low-dose irradiation, they undergo mitotic arrest followed by p53-dependent apoptosis, whereas the other cell types simply arrest. This protective mechanism, active exclusively after E5.5 and lost during gastrulation, ensures the elimination of every mutated cell before its clonal expansion and is therefore expected to greatly increase fitness. We show that the insurgence of apoptosis relies on the epiblastspecific convergence of both increased DNA damage signalling and stronger pro-apoptotic balance. Although upstream Atm/Atr global activity and specific γH2AX phosphorylation are similar in all cell types of the embryo, 53BP1 recruitment at DNA breaks is immediately amplified only in epiblast cells after ionizing radiation. This correlates with rapid epiblast-specific activation of p53 and its transcriptional properties. Moreover, between E5.5 and E6.5 epiblast cells lower their apoptotic threshold by enhancing the expression of pro-apoptotic Bak and Bim and repressing the anti-apoptotic Bcl-xL. Thus, even after low-dose irradiation, the cytoplasmic priming of epiblast cells allows p53 to rapidly induce apoptosis via a partially transcription-independent mechanism.

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“…1). In addition, ATM can respond to non-DNA-damaging stresses and has recently been described as having a role in neoangiogenesis in a melanoma model (2)(3)(4)(5). DNA damage leads to activation of ATM kinase activity and thus phosphorylation of a myriad of downstream targets, including p53, CHK2, and KAP-1 (6,7).…”

Section: The Role Of Atm In Damage Responsementioning

confidence: 99%

Radiation and ATM inhibition: the heart of the matter

Hammond¹,

Muschel²

2014

J. Clin. Invest.

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C o m m e n t a r y 3 2 8 9 jci.org Volume 124 Number 8 August 2014Radiation and ATM inhibition: the heart of the matter The role of ATM in damage responseThe ataxia telangiectasia mutated (ATM) kinase is a member of the PI3K-like protein kinase (PIKK) family with extensive roles in DNA damage response signaling (reviewed in ref. 1). In addition, ATM can respond to non-DNA-damaging stresses and has recently been described as having a role in neoangiogenesis in a melanoma model (2-5). DNA damage leads to activation of ATM kinase activity and thus phosphorylation of a myriad of downstream targets, including p53, CHK2, and KAP-1 (6, 7). This activation triggers cell cycle checkpoints, arrest, and delays in the G 1 , S, and G 2 phases of the cell cycle and enables DNA repair of double-stranded breaks both by homologous recombination and by nonhomologous end joining (8, 9). Hence, fibroblasts and tumor cells are radiosensitized to X-ray radiation therapy (XRT) in culture by pharmacological ATM inhibition, or by ATM mutation and deletion (10). These data suggest that inhibition of ATM should radiosensitize tumors; however, there is a hesitancy to employ this strategy clinically, due to fears that normal tissues could be substantially sensitized as well. This reluctance is well founded, as it is based on the catastrophic response of patients with ataxia telangiectasia (AT) to XRT. The AT syndrome, which is now characterized in part by extreme radiosensitivity, is caused by mutations in the ATM gene. Before AT was fully characterized, a few patients who developed lymphoma (a frequent event in AT) were radiated to treat mediastinal cancers and suffered drastic side effects. Those few reports stressed severe mucositis of the esophagus and skin desquamation (e.g., ref.11). This led to the subsequently proven supposition that ATM plays an important role in the response and repair of DNA damage, but also the understandable reticence of clinicians to consider XRT for AT patients and reluctance to use AT inhibitors because of the potential normal tissue sensitivity. While the clinical observations point to mucous membranes and skin as targets for deleterious normal tissue effects, it should be remembered that thoracic radiation also inevitably results in some radiation dose to the heart. Work over recent years has shown that irradiation of the heart during treatment for breast cancer leads to long-term increased risk for atherosclerotic coronary disease (12). However, this dose-dependent pathology evolves over the long term and is not replicated in mice unless they are also predisposed to atherosclerosis, as in mice with ApoE deficiency (13), and so might not emerge in some model systems. An elegant model to understand the role of ATMIn this issue, Moding et al. used an innovative and intricate system to distinguish the effects of ATM deletion in endothelium from the heart and from tumors (14). The authors used a sarcoma model that they previously established in mice with mutant Kras G12D and p53 flanked by inactivating stop ...

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Replication Stress and Chromatin Context Link ATM Activation to a Role in DNA Replication

Cited by 107 publications

References 42 publications

ATM and ATR signaling at a glance

ATM and ATR signaling at a glance

Differential DNA damage signalling and apoptotic threshold correlate with mouse epiblast-specific hypersensitivity to radiation

Radiation and ATM inhibition: the heart of the matter

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