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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defects in the DNA damage response pathways can lead to tumour development. The tumour suppressor p53 is a key player in the DNA damage response, and the precise regulation of p53 is critical for the suppression of tumorigenesis. DNA damage induces the activity of p53, via damage sensors such as ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia-related), which leads to the transcriptional regulation of a variety of genes involved in cell cycle control and apoptosis. p53 is therefore tightly controlled, and its activity is regulated at a multiplicity of levels. An increasing array of cofactors are now known to influence p53 activity. Here we will discuss several of the cofactors that impact on p53 activity, specifically those involved in the function of the two novel p53 cofactors JMY (junction-mediating and regulatory protein) and Strap (serine/threonine-kinase-receptor-associated protein).
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PMID:The p53 response during DNA damage: impact of transcriptional cofactors. 1662 98

The BRCA1 tumour suppressor and its heterodimeric partner BARD1 constitute an E3-ubiquitin (Ub) ligase and function in DNA repair by unknown mechanisms. We show here that the Caenorhabditis elegans BRCA1/BARD1 (CeBCD) complex possesses an E3-Ub ligase responsible for ubiquitylation at DNA damage sites following ionizing radiation (IR). The DNA damage checkpoint promotes the association of the CeBCD complex with E2-Ub conjugating enzyme, Ubc5(LET-70), leading to the formation of an active E3-Ub ligase on chromatin following IR. Correspondingly, defects in Ubc5(let-70) or the DNA damage checkpoint genes atl-1 or mre-11 abolish CeBCD-dependent ubiquitylation in vivo. Extending these findings to human cells reveals a requirement for UbcH5c, the MRN complex, gamma-H2AX and a co-dependence for ATM and ATR kinases for BRCA1-dependent ubiquitylation at DNA damage sites. Furthermore, we demonstrate that the DNA damage checkpoint promotes the association between BRCA1 and UbcH5c to form an active E3-Ub ligase on chromatin after IR. These data reveal that BRCA1-dependent ubiquitylation is activated at sites of DNA repair by the checkpoint as part of a conserved DNA damage response.
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PMID:A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites. 1662 14

When the genomic integrity of a cell is challenged, its fate is determined in part by signals conveyed by the p53 tumour suppressor protein. It was observed recently that such signals are not simple gradations of p53 concentration, but rather a counter-intuitive limit-cycle behaviour. Based on a careful mathematical interpretation of the experimental body of knowledge, we propose a model for the p53 signalling network and characterise the p53 stability and oscillatory dynamics. In our model, ATM, a protein that senses DNA damage, activates p53 by phosphorylation. In its active state, p53 has a decreased degradation rate and an enhanced transactivation of Mdm2, a gene whose protein product Mdm2 tags p53 for degradation. Thus the p53-Mdm2 system forms a negative feedback loop. However, the feedback in this loop is delayed, as the pool of Mdm2 molecules being induced by p53 at a given time will mark for degradation the pool of p53 molecules at some later time, after the Mdm2 molecules have been transcribed, exported out of the nucleus, translated and transported back into the nucleus. The analysis of our model demonstrates how this time lag combines with the ATM-controlled feedback strength and effective dampening of the negative feedback loop to produce limit-cycle oscillations. The picture that emerges is that ATM, once activated by DNA damage, makes the p53-Mdm2 oscillator undergo a supercritical Hopf bifurcation. This approach yields an improved understanding of the global dynamics and bifurcation structure of our time-delayed, negative feedback model and allows for predictions of the behaviour of the p53 system under different perturbations.
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PMID:p53-Mdm2 loop controlled by a balance of its feedback strength and effective dampening using ATM and delayed feedback. 1698 75

The 53BP1 tumour suppressor, an important regulator of genome stability, is phosphorylated in response to ionising radiation (IR) by the ATM protein kinase, itself an important regulator of cellular responses to DNA damage. The only known sites of phosphorylation in 53BP1 are Ser25 and/or Ser29 but 53BP1 lacking these residues is still phosphorylated after DNA damage. In this study, we use mass spectrometry-based together with bioinformatic analysis to identify novel DNA damage-regulated sites of 53BP1 phosphorylation. Several new sites were identified that conform to the consensus Ser/Thr-Gln motif phosphorylated by ATM and related kinases. Phospho-specific antibodies were raised, and were used to demonstrate ATM-dependent phosphorylation of these residues in 53BP1 after exposure of cells to IR. Surprisingly, 53BP1 was also phosphorylated on these residues after exposure of cells to UV light. In this case, 53BP1 phosphorylation did not require ATM but required ATR instead. These data reveal that 53BP1 is phosphorylated on multiple residues in response to different types of DNA damage, and that 53BP1 is regulated by ATR in response to UV-induced DNA damage.
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PMID:Characterisation of the sites of DNA damage-induced 53BP1 phosphorylation catalysed by ATM and ATR. 2944 68

Human (h)PTIP plays important but poorly understood roles in cellular responses to DNA damage. hPTIP interacts with 53BP1 tumour suppressor but only when 53BP1 is phosphorylated by ATM after DNA damage although the mechanism(s) and significance of the interaction of these two proteins are unclear. Here, we pinpoint a single ATM-phosphorylated residue in 53BP1--Ser25--that is required for binding of 53BP1 to hPTIP. Binding of phospho-Ser25 to hPTIP in vitro and in vivo requires two closely apposed pairs of BRCT domains at the C-terminus of hPTIP and neither pair alone can bind to phospho-Ser25, even though one of these BRCT pairs in isolation can bind to other ATM-phosphorylated epitopes. Mutations in 53BP1 and in hPTIP that prevent the interaction of the two proteins, render cells hypersensitive to DNA damage and weaken ATM signalling. The C-terminal BRCT domains of hPTIP are also required for stable retention of hPTIP at sites of DNA damage but this appears to be independent of binding to 53BP1. Thus, the BRCT domains of hPTIP play important roles in the cellular response to DNA damage.
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PMID:Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage. 2913 88

The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P=0.0003) and BRCA2 (30%; P=0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P=0.0002), progesterone receptor (PR) negative (P=0.004) and were of higher grade (P=0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P=0.0006) and p53 was overabundant (47%; P<0.0000000001) among the difficult-to-treat ER/PR/ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.
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PMID:The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. 1798 90

The tumour suppressor HIPK2 is an important regulator of cell death induced by DNA damage, but how its activity is regulated remains largely unclear. Here we demonstrate that HIPK2 is an unstable protein that colocalizes and interacts with the E3 ubiquitin ligase Siah-1 in unstressed cells. Siah-1 knockdown increases HIPK2 stability and steady-state levels, whereas Siah-1 expression facilitates HIPK2 polyubiquitination, degradation and thereby inactivation. During recovery from sublethal DNA damage, HIPK2, which is stabilized on DNA damage, is degraded through a Siah-1-dependent, p53-controlled pathway. Downregulation of Siah-1 inhibits HIPK2 degradation and recovery from damage, driving the cells into apoptosis. We have also demonstrated that DNA damage triggers disruption of the HIPK2-Siah-1 complex, resulting in HIPK2 stabilization and activation. Disruption of the HIPK2-Siah-1 complex is mediated by the ATM/ATR pathway and involves ATM/ATR-dependent phosphorylation of Siah-1 at Ser 19. Our results provide a molecular framework for HIPK2 regulation in unstressed and damaged cells.
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PMID:Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. 1853 14

Hereditary breast cancer accounts for up to 5-10% of all breast carcinomas. Recent studies have demonstrated that mutations in two high-penetrance genes, namely BRCA1 and BRCA2, are responsible for about 16% of the familial risk of breast cancer. Even though subsequent studies have failed to find another high-penetrance breast cancer susceptibility gene, several genes that confer a moderate to low risk of breast cancer development have been identified; moreover, hereditary breast cancer can be part of multiple cancer syndromes. In this review we will focus on the hereditary breast carcinomas caused by mutations in BRCA1, BRCA2, Fanconi anaemia (FANC) genes, CHK2 and ATM tumour suppressor genes. We describe the hallmark histological features of these carcinomas compared with non-hereditary breast cancers and show how an accurate histopathological diagnosis may help improve the identification of patients to be screened for mutations. Finally, novel therapeutic approaches to treat patients with BRCA1 and BRCA2 germ line mutations, including cross-linking agents and PARP inhibitors, are discussed.
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PMID:Hereditary breast cancer: from molecular pathology to tailored therapies. 1868 20

DNA repair pathways enable tumour cells to survive DNA damage induced by external agents such as therapeutic treatments. Signalling cascades involved in these pathways comprise the DNA-dependent protein kinase (DNA-PK), Ataxia-telangiectasia mutated (ATM), ATM and Rad3 related (ATR) and checkpoint kinases I and 2 (Chk1/Chk2), among others. ATM and ATR phosphorylate, respectively, Chk2 and Chk1, leading to activation of checkpoints. Chk2 acts as a signal distributor, dispersing checkpoint signal to downstream targets such as p53, Cdc25A, Cdc25C, BRCA1 and E2F1. A role of Chk2 as a candidate tumour suppressor has been suggested based on both mouse genetics and somatic tumour studies. We will discuss here the possible role of this kinase in human carcinogenesis and the possibility to use it as a target to increment DNA damage in cancer cells in response to DNA-damaging therapies.
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PMID:Role of CHK2 in cancer development. 1879 70

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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PMID:Somatic mutations affect key pathways in lung adenocarcinoma. 1894 47


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