DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation

Bakkenist, Christopher J.; Kastan, Michael B.

doi:10.1038/nature01368

Cited by 3,042 publications

(2,893 citation statements)

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“…p53-dependent S-phase DNA damage checkpoint T Shimura et al repair foci), which include PCNA (Karmakar et al, 2001;Solomon et al, 2004). The relationship between gamma-irradiation induced PCNA foci and DNA repair foci was studied by analyzing focus formation of g-H2AX and phospho-ATM which accumulate at DNA double strand beaks (Bakkenist and Kastan, 2003;Pilch et al, 2003;Sedelnikova et al, 2003). Interestingly, PCNA foci did not co-localize with g-H2AX foci and phospho-ATM foci after low-dose irradiation of WT MEFs (Figure 3c).…”

Section: Resultsmentioning

confidence: 99%

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

et al. 2006

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The S-phase DNA damage checkpoint is activated by DNA damage to delay DNA synthesis allowing time to resolve the replication block. We previously discovered the p53-dependent S-phase DNA damage checkpoint in mouse zygotes fertilized with irradiated sperm. Here, we report that the same p53 dependency holds in mouse embryonic fibroblasts (MEFs) at low doses of irradiation. DNA synthesis in p53 wild-type (WT) MEFs was suppressed in a biphasic manner in which a sharp decrease below 2.5 Gy was followed by a more moderate decrease up to 10 Gy. In contrast, p53À/À MEFs exhibited radioresistant DNA synthesis below 2.5 Gy whereas the cells retained the moderate suppression above 5 Gy. DNA fiber analysis revealed that 1 Gy irradiation suppressed replication fork progression in p53 WT MEFs, but not in p53À/À MEFs. Proliferating cell nuclear antigen (PCNA), clamp loader of DNA polymerase, was phosphorylated in WT MEFs after 1 Gy irradiation and redistributed to form foci in the nuclei. In contrast, PCNA was not phosphorylated and dissociated from chromatin in 1 Gy-irradiated p53À/À MEFs. These results demonstrate that the novel low-dosespecific p53-dependent S-phase DNA damage checkpoint is likely to regulate the replication fork movement through phosphorylation of PCNA.

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Section: Resultsmentioning

confidence: 99%

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

et al. 2006

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“…ATM, the gene that is mutated in the hereditary disease ataxia-telangiectasia, codes for a protein kinase that acts as a master regulator of cellular responses to DNA double-strand breaks (Bakkenist and Kastan, 2003). ATM is activated in the event of DNA damage -for example, due to exposure to ionising radiation.…”

Section: Discussionmentioning

confidence: 99%

“…Detailed data on the antibodies are given in Table 1. For three of the four proteins being analysed -that is, p53, ATM, and CHK2 -antibodies were used that detect phosphorylation at specific amino-acid residues that indicate functional activity (ATM, CHK2) (Bakkenist and Kastan 2003;Bartkova et al, 2005) or resistance against inactivation (p53) (Shieh et al, 1997). The reaction was developed using the labelled streptavidinbiotin -alkaline phosphatase system, with fast red as chromogen.…”

Section: Immunohistochemical Investigations Based On Pretherapeutic Tmentioning

confidence: 99%

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

et al. 2007

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Pretherapeutic identification of oesophageal squamous cell carcinomas that will respond to neoadjuvant chemoradiotherapy is an important attempt for improvement of patient's prognosis. In the current study, pretherapeutic biopsies from 94 oesophageal squamous cell carcinomas (cT3, cN0/ þ , cM0) in patients who underwent neoadjuvant chemoradiotherapy (RCTx: 45 Gy plus cisplatin and 5-fluorouracil) and subsequent oesophagectomy in the setting of a single-centre prospective treatment trial were investigated by means of immunohistochemistry. Expression of proteins involved in DNA repair and/or cell-cycle regulation, that is p53, p53 (phosphorylated at Ser15), EGFR, ATM protein kinase (phosphorylated at Ser1981) and checkpoint kinase 2 (CHK2) (phosphorylated at Thr68) was correlated with the response to RCTx and with overall survival. Tumours that were positive for CHK2 expression more frequently showed clinically determined regression after RCTx (69.4%) than tumours that were negative for CHK2 expression (32.1%; P ¼ 0.0011), whereas other parameters did not correlate with tumour regression. Expression of ATM correlated with expression of CHK2 (P ¼ 0.0061) and p53-phospho (P ¼ 0.0064). Expression of p53 correlated with expression of p53-phospho (Po0.0001). In contrast to clinical and histopathological response evaluation, none of the molecular parameters under investigation correlated with overall survival. In conclusion, expression analysis of p53, EGFR CHK2 and ATM has no predictive value in multimodally treated oesophageal squamous cell carcinoma.

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“…Also, ATM could start another important DNA repair of homologous recombination repair (HRR) 39. DNA damage activates ATM through intermolecular autophosphorylation (phospho S1981) and dimer dissociation 40. Inhibition of ATM or pATM (phospho S1981) could radiosensitize cancer cells 20, 41, 42, 43.…”

Section: Discussionmentioning

confidence: 99%

Radiosensitizing effects of miR‐18a‐5p on lung cancer stem‐like cells via downregulating both ATM and HIF‐1α

Chen

et al. 2018

Cancer Medicine

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Lung cancer is one of the main causes of cancer mortality globally. Most patients received radiotherapy during the course of disease. However, radioresistance generally occurs in the majority of these patients, leading to poor curative effect, and the underlying mechanism remains unclear. In the present study, miR‐18a‐5p expression was downregulated in irradiated lung cancer cells. Overexpression of miR‐18a‐5p increased the radiosensitivity of lung cancer cells and inhibited the growth of A549 xenografts after radiation exposure. Dual luciferase report system and miR‐18a‐5p overexpression identified ataxia telangiectasia mutated (ATM) and hypoxia inducible factor 1 alpha (HIF‐1α) as the targets of miR‐18a‐5p. The mRNA and protein expressions of ATM and HIF‐1α were dramatically downregulated by miR‐18a‐5p in vitro and in vivo. Clinically, plasma miR‐18a‐5p expression was significantly higher in radiosensitive than in radioresistant group (P < .001). The cutoff value of miR‐18a‐5p >2.28 was obtained from receiver operating characteristic (ROC) curve. The objective response rate (ORR) was significantly higher in miR‐18a‐5p‐high group than in miR‐18a‐5p‐low group (P < .001). A tendency demonstrated that the median local progression‐free survival (PFS) from radiotherapy was longer in miR‐18a‐5p‐high than in miR‐18a‐5p‐low group (P = .082). The median overall survival (OS) from radiotherapy was numerically longer in miR‐18a‐5p‐high than in miR‐18a‐5p‐low group (P = .281). The sensitivity and specificity of plasma miR‐18a‐5p to predict radiosensitivity was 87% and 95%, respectively. Collectively, these results indicate that miR‐18a‐5p increases the radiosensitivity in lung cancer cells and CD133+ stem‐like cells via downregulating ATM and HIF‐1α expressions. Plasma miR‐18a‐5p would be an available indicator of radiosensitivity in lung cancer patients.

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DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation

Cited by 3,042 publications

References 46 publications

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

Radiosensitizing effects of miR‐18a‐5p on lung cancer stem‐like cells via downregulating both ATM and HIF‐1α

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