Gene Summary

Gene:ATM; ATM serine/threonine kinase
Summary:The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:serine-protein kinase ATM
Source:NCBIAccessed: 18 March, 2015


What does this gene/protein do?
Show (50)
Pathways:What pathways are this gene/protein implicaed in?
Show (13)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 18 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 18 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ATM (cancer-related)

Mao A, Liu Y, Zhang H, et al.
microRNA expression and biogenesis in cellular response to ionizing radiation.
DNA Cell Biol. 2014; 33(10):667-79 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Increasing evidence demonstrates that the expression levels of microRNAs (miRNAs) significantly change upon ionizing radiation (IR) and play a critical role in cellular response to IR. Although several radiation responsive miRNAs and their targets have been identified, little is known about how miRNAs expression and biogenesis is regulated by IR-caused DNA damage response (DDR). Hence, in this review, we summarize miRNA expression and biogenesis in cellular response to IR and mainly elucidate the regulatory mechanisms of miRNA expression and biogenesis from different aspects including ataxia-telangiectasia mutated (ATM) kinase, p53/p63/p73 family and other potential factors. Furthermore, we focus on ΔNp73, which might be a potential regulator of miRNA expression and biogenesis in cellular response to IR. miRNAs could effectively activate the IR-induced DDR and modulate the radiation response and cellular radiosensitivity, which have an important potential clinical application. Therefore, thoroughly understanding the regulatory mechanisms of miRNAs expression and biogenesis in radiation response will provide new insights for clinical cancer radiotherapy.

Cheung CT, Singh R, Kalra RS, et al.
Collaborator of ARF (CARF) regulates proliferative fate of human cells by dose-dependent regulation of DNA damage signaling.
J Biol Chem. 2014; 289(26):18258-69 [PubMed] Article available free on PMC after 27/06/2015 Related Publications
Collaborator of ARF (CARF) has been shown to directly bind to and regulate p53, a central protein that controls tumor suppression via cellular senescence and apoptosis. However, the cellular functions of CARF and the mechanisms governing its effect on senescence, apoptosis, or proliferation are still unknown. Our previous studies have shown that (i) CARF is up-regulated during replicative and stress-induced senescence, and its exogenous overexpression caused senescence-like growth arrest of cells, and (ii) suppression of CARF induces aneuploidy, DNA damage, and mitotic catastrophe, resulting in apoptosis via the ATR/CHK1 pathway. In the present study, we dissected the cellular role of CARF by investigating the molecular pathways triggered by its overexpression in vitro and in vivo. We found that the dosage of CARF is a critical factor in determining the proliferation potential of cancer cells. Most surprisingly, although a moderate level of CARF overexpression induced senescence, a very high level of CARF resulted in increased cell proliferation. We demonstrate that the level of CARF is crucial for DNA damage and checkpoint response of cells through ATM/CHK1/CHK2, p53, and ERK pathways that in turn determine the proliferative fate of cancer cells toward growth arrest or proproliferative and malignant phenotypes. To the best of our knowledge, this is the first report that demonstrates the capability of a fundamental protein, CARF, in controlling cell proliferation in two opposite directions and hence may play a key role in tumor biology and cancer therapeutics.

Rao F, Cha J, Xu J, et al.
Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2.
Mol Cell. 2014; 54(1):119-32 [PubMed] Article available free on PMC after 10/04/2015 Related Publications
The apoptotic actions of p53 require its phosphorylation by a family of phosphoinositide-3-kinase-related-kinases (PIKKs), which include DNA-PKcs and ATM. These kinases are stabilized by the TTT (Tel2, Tti1, Tti2) cochaperone family, whose actions are mediated by CK2 phosphorylation. The inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in p53-associated cell death. In the present study we report an apoptotic signaling cascade linking CK2, TTT, the PIKKs, and p53. We demonstrate that IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the TTT complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine 15 to activate the cell death program in human cancer cells and in murine B cells.

Mohanty S, Saha S, Md S Hossain D, et al.
ROS-PIASγ cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors.
Cell Death Dis. 2014; 5:e1021 [PubMed] Article available free on PMC after 10/04/2015 Related Publications
With the existing knowledge of ATM's role in therapeutic resistance, the present study aimed at identifying the molecular mechanisms that influence ATM to oscillate between chemoresistance and chemosensitivity. We observed that the redox status of tumors functions as a major determinant of ATM-dependent 'resistance-to-apoptosis' molecular switch. At a low reactive oxygen species (ROS) condition during genotoxic insult, the ATM/sumoylated-IKKγ interaction induced NFκB activation that resisted JNK-mediated apoptosis, whereas increasing cellular ROS restored ATM/JNK apoptotic signaling. A search for the upstream missing link revealed that high ROS induces oxidation and ubiquitin-mediated degradation of PIASγ, thereby disrupting PIASγ-IKKγ cross talk, a pre-requisite for IKKγ sumoylation and subsequent NFκB activation. Interruption in the PIASγ-mediated resistance pathway channels ATM signaling toward ATM/JNK pro-death circuitry. These in vitro results also translated to sensitive and resistant tumor allograft mouse models in which low ROS-induced resistance was over-ruled in PIASγ knockout tumors, while its overexpression inhibited high ROS-dependent apoptotic cues. Cumulatively, our findings identified an unappreciated yet critical combinatorial function of cellular ROS and PIASγ in regulating ATM-mediated chemosensitization of resistant tumors. Thus, therapeutic strategies employing ROS upregulation to inhibit PIASγ during genotoxic therapy may, in future, help to eliminate the problems of NFκB-mediated tumor drug resistance.

Zhang D, Wang H, Sun M, et al.
Speckle-type POZ protein, SPOP, is involved in the DNA damage response.
Carcinogenesis. 2014; 35(8):1691-7 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Speckle-type POZ protein (SPOP) is an adaptor of the cullin 3-based ubiquitin ligase responsible for the degradation of oncoproteins frequently overexpressed in many tumor cells. Altered expression and somatic mutations of SPOP have been observed in various tumor types with chromosomal aberrations, indicating a role of SPOP in maintaining genome stability, although a detailed mechanism remains unclear. Here, we show that SPOP is a component of the DNA damage response (DDR). SPOP is recruited to DNA double-strand break sites and it forms nuclear foci after DNA damage. SPOP foci colocalize with γ-H2AX foci and are predominantly dependent on the activity of the ataxia-telangiectasia mutated (ATM) kinase. Furthermore, SPOP interacts with ATM in response to DNA damage. Finally, we demonstrate that knocking down of SPOP resulted in an impaired DDR and a hypersensitivity to ionizing irradiation. Together, we highlight a critical role of SPOP in the DDR.

Filipponi D, Bulavin D
Wip1 and ATM in tumor evolution: role for BRCA1.
Oncotarget. 2013; 4(12):2170 [PubMed] Article available free on PMC after 01/08/2015 Related Publications

Thurn KT, Thomas S, Raha P, et al.
Histone deacetylase regulation of ATM-mediated DNA damage signaling.
Mol Cancer Ther. 2013; 12(10):2078-87 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Ataxia-telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A, and RRM2B that promote cell-cycle arrest and DNA repair. The upregulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here, we show that histone deacetylases (HDAC) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors.

Regal JA, Festerling TA, Buis JM, Ferguson DO
Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms.
Hum Mol Genet. 2013; 22(25):5146-59 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
DNA double-strand breaks (DSBs) can lead to instability of the genome if not repaired correctly. The MRE11/RAD50/NBS1 (MRN) complex binds DSBs and initiates damage-induced signaling cascades via activation of the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia- and rad3-related (ATR) kinases. Mutations throughout MRE11 cause ataxia-telangiectasia-like disorder (ATLD) featuring cerebellar degeneration, and cancer-predisposition in certain kindreds. Here, we have examined the impact on DNA damage signaling of several disease-associated MRE11A alleles to gain greater understanding of the mechanisms underlying the diverse disease sequelae of ATLD. To this end, we have designed a system whereby endogenous wild-type Mre11a is conditionally deleted and disease-associated MRE11 mutants are stably expressed at physiologic levels. We find that mutations in the highly conserved N-terminal domain impact ATM signaling by perturbing both MRE11 interaction with NBS1 and MRE11 homodimerization. In contrast, an inherited allele in the MRE11 C-terminus maintains MRN interactions and ATM/ATR kinase activation. These findings reveal that ATLD patients have reduced ATM activation resulting from at least two distinct mechanisms: (i) N-terminal mutations destabilize MRN interactions, and (ii) mutation of the extreme C-terminus maintains interactions but leads to low levels of the complex. The N-terminal mutations were found in ATLD patients with childhood cancer; thus, our studies suggest a clinically relevant dichotomy in MRE11A alleles. More broadly, these studies underscore the importance of understanding specific effects of hypomorphic disease-associated mutations to achieve accurate prognosis and appropriate long-term medical surveillance.

Bakkenist CJ, Czambel RK, Clump DA, et al.
Radiation therapy induces the DNA damage response in peripheral blood.
Oncotarget. 2013; 4(8):1143-8 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Stereotactic body radiation therapy (SBRT) is a radiotherapy modality that delivers highly conformal, ablative doses to a well-defined target. Here, using a semiquantitative multiplexed assay to analyze ATM and H2AX phosphorylation, we show that ATM kinase activity in peripheral blood mononuclear cells is induced following SBRT. This observation of a systemic ATM kinase-dependent DNA damage response in the peripheral blood is unprecedented and promotes the use of ATM serine-1981 phosphorylation as a predictive biomarker for DNA damaging modalities and ATM inhibitors.

Cremona CA, Behrens A
ATM signalling and cancer.
Oncogene. 2014; 33(26):3351-60 [PubMed] Related Publications
ATM, the protein kinase mutated in the rare human disease ataxia telangiectasia (A-T), has been the focus of intense scrutiny over the past two decades. Initially this was because of the unusual radiosensitive phenotype of cells from A-T patients, and latterly because investigating ATM signalling has yielded valuable insights into the DNA damage response, redox signalling and cancer. With the recent explosion in genomic data, ATM alterations have been revealed both in the germline as a predisposing factor for cancer and as somatic changes in tumours themselves. Here we review these findings, as well as advances in the understanding of ATM signalling mechanisms in cancer and ATM inhibition as a strategy for cancer treatment.

Muraki K, Han L, Miller D, Murnane JP
The role of ATM in the deficiency in nonhomologous end-joining near telomeres in a human cancer cell line.
PLoS Genet. 2013; 9(3):e1003386 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Telomeres distinguish chromosome ends from double-strand breaks (DSBs) and prevent chromosome fusion. However, telomeres can also interfere with DNA repair, as shown by a deficiency in nonhomologous end joining (NHEJ) and an increase in large deletions at telomeric DSBs. The sensitivity of telomeric regions to DSBs is important in the cellular response to ionizing radiation and oncogene-induced replication stress, either by preventing cell division in normal cells, or by promoting chromosome instability in cancer cells. We have previously proposed that the telomeric protein TRF2 causes the sensitivity of telomeric regions to DSBs, either through its inhibition of ATM, or by promoting the processing of DSBs as though they are telomeres, which is independent of ATM. Our current study addresses the mechanism responsible for the deficiency in repair of DSBs near telomeres by combining assays for large deletions, NHEJ, small deletions, and gross chromosome rearrangements (GCRs) to compare the types of events resulting from DSBs at interstitial and telomeric DSBs. Our results confirm the sensitivity of telomeric regions to DSBs by demonstrating that the frequency of GCRs is greatly increased at DSBs near telomeres and that the role of ATM in DSB repair is very different at interstitial and telomeric DSBs. Unlike at interstitial DSBs, a deficiency in ATM decreases NHEJ and small deletions at telomeric DSBs, while it increases large deletions. These results strongly suggest that ATM is functional near telomeres and is involved in end protection at telomeric DSBs, but is not required for the extensive resection at telomeric DSBs. The results support our model in which the deficiency in DSB repair near telomeres is a result of ATM-independent processing of DSBs as though they are telomeres, leading to extensive resection, telomere loss, and GCRs involving alternative NHEJ.

Kilpivaara O, Aaltonen LA
Diagnostic cancer genome sequencing and the contribution of germline variants.
Science. 2013; 339(6127):1559-62 [PubMed] Related Publications
Whole-genome sequencing (WGS) is revolutionizing medical research and has the potential to serve as a powerful and cost-effective diagnostic tool in the management of cancer. We review the progress to date in the use of WGS to reveal how germline variants and mutations may be associated with cancer. We use colorectal cancer as an example of how the current level of knowledge can be translated into predictions of predisposition. We also address challenges in the clinical implementation of the variants in germline DNA identified through cancer genome sequencing. We call for the international development of standards to facilitate the clinical use of germline information arising from diagnostic cancer genome sequencing.

Tang J, Agrawal T, Cheng Q, et al.
Phosphorylation of Daxx by ATM contributes to DNA damage-induced p53 activation.
PLoS One. 2013; 8(2):e55813 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
p53 plays a central role in tumor suppression. It does so by inducing anti-proliferative processes as a response to various tumor-promoting stresses. p53 is regulated by the ubiquitin ligase Mdm2. The optimal function of Mdm2 requires Daxx, which stabilizes Mdm2 through the deubiquitinase Hausp/USP7 and also directly promotes Mdm2's ubiquitin ligase activity towards p53. The Daxx-Mdm2 interaction is disrupted upon DNA damage. However, both the mechanisms and the consequence of the Daxx-Mdm2 dissociation are not understood. Here we show that upon DNA damage Daxx is phosphorylated in a manner that is dependent on ATM, a member of the PI 3-kinase family that orchestrates the DNA damage response. The main phosphorylation site of Daxx is identified to be Ser564, which is a direct target of ATM. Phosphorylation of endogenous Daxx at Ser564 occurs rapidly during the DNA damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of Daxx from Mdm2, stabilizes Mdm2, and inhibits DNA damage-induced p53 activation. These results suggest that phosphorylation of Daxx by ATM upon DNA damage disrupts the Daxx-Mdm2 interaction and facilitates p53 activation.

Wang Y, Taniguchi T
MicroRNAs and DNA damage response: implications for cancer therapy.
Cell Cycle. 2013; 12(1):32-42 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
The DNA damage response (DDR) pathways play critical roles in protecting the genome from DNA damage. Abrogation of DDR often results in elevated genomic instability and cellular sensitivity to DNA damaging agents. Many proteins involved in DDR are subjected to precise regulation at multiple levels, such as transcriptional control and posttranslational modifications, in response to DNA damage. MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. The expression levels of some miRNAs change in response to DNA damage. Some miRNAs, such as miR-24, 138, 96 and 182, have been implicated in DDR and/or DNA repair and affect cellular sensitivity to DNA damaging agents. In this review, we summarize recent findings related to the emerging roles of miRNAs in regulating DDR and DNA repair and discuss their potential in cancer therapy.

Huang H, Xiao T, He L, et al.
Interferon-β-armed oncolytic adenovirus induces both apoptosis and necroptosis in cancer cells.
Acta Biochim Biophys Sin (Shanghai). 2012; 44(9):737-45 [PubMed] Related Publications
Interferon-β (IFN-β) has been widely used in cancer therapy, but the clinical trial results are generally disappointing. Our previous studies have shown that an oncolytic adenovirus carrying IFN-β (ZD55-IFN-β) exhibits significant anti-tumor activities. However, the underlying mechanisms are not clear. Here we showed that ZD55-IFN-β infection-induced S-phase cell cycle arrest in a p53-dependent manner by activating the ataxia telangiectasia mutated-dependent DNA damage pathway. In addition, ZD55-IFN-β infection could initiate both caspase-dependent apoptosis and necroptosis in cancer cells. More importantly, ZD55-IFN-β showed a synergistic effect on cancer cells when combined with doxorubicin. These results suggest that the combination of ZD55-IFN-β with doxorubicin may represent a promising clinical strategy in cancer therapy.

Xu Y, Xu C, Price BD
Mechanistic links between ATM and histone methylation codes during DNA repair.
Prog Mol Biol Transl Sci. 2012; 110:263-88 [PubMed] Related Publications
The ataxia telangiectasia-mutated (ATM) protein kinase is the master regulator of the DNA double-strand break (DSB) repair pathway. The activation of ATM involves its recruitment to the DSB through interaction with the mre11-rad50-nbs1 complex, followed by the acetylation of ATM by the Tip60 acetyltransferase. This acetylation of ATM within its regulatory domain is essential for activating ATM's kinase activity. Further work has now revealed that Tip60 is activated through direct interaction between Tip60's chromodomain and histone H3 trimethylated on lysine 9 (H3K9me3). The loading of Tip60 onto the chromatin at DSBs therefore represents the primary mechanism for activation of Tip60's acetyltransferase activity in response to DNA damage. The ability of H3K9me3 at DSBs to regulate the activity of Tip60 and the subsequent activation of ATM emphasizes the crucial role played by chromatin architecture in regulating DSB repair. Further, histone methylation and chromatin structure are disrupted in human cancers, implying that altered chromatin structure in tumor cells may impact DSB repair, increasing genomic instability and contributing to the progression of cancer.

Basu B, Yap TA, Molife LR, de Bono JS
Targeting the DNA damage response in oncology: past, present and future perspectives.
Curr Opin Oncol. 2012; 24(3):316-24 [PubMed] Related Publications
PURPOSE OF REVIEW: The success of poly(ADP-ribose) polymerase inhibition in BRCA1 or BRCA2 deficient tumors as an anticancer strategy provided proof-of-concept for a synthetic lethality approach in oncology. There is therefore now active interest in expanding this approach to include other agents targeting the DNA damage response (DDR). We review lessons learnt from the development of inhibitors against DNA damage response mechanisms and envision the future of DNA repair inhibition in oncology.
RECENT FINDINGS: Preclinical synthetic lethality screens may potentially identify the best combinations of DNA-damaging drugs with inhibitors of DNA repair and the DDR or two agents acting within the DDR. Efforts are currently being made to establish robust and cost-effective assays that may be implemented within appropriate time-scales in parallel with future clinical studies. Detection of relevant mutations in a high-throughput manner, such as with next-generation sequencing for genes implicated in homologous recombination, including BRCA1, BRCA2, and ataxia telangiectasia mutated is anticipated. Novel approaches targeting the DDR are currently being evaluated and inhibitors of ATM, RAD51 and DNA-dependent protein kinase are now in early drug discovery and development.
SUMMARY: There remains great enthusiasm in oncology practice for pursuing the strategy of synthetic lethality. The future development of antitumor agents targeting the DDR should include detailed correlative biomarker work within early phase clinical studies wherever possible, with clear attempts to identify doses at which robust target modulation is observed.

Fillon M
Gene linked to pancreatic cancer.
J Natl Cancer Inst. 2012; 104(6):438-9 [PubMed] Related Publications

Hu J, Hwang SS, Liesa M, et al.
Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer.
Cell. 2012; 148(4):651-63 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm(-/-) mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1β, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1β or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy.

Zhao L, Gu A, Ji G, et al.
The association between ATM IVS 22-77 T>C and cancer risk: a meta-analysis.
PLoS One. 2012; 7(1):e29479 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND AND OBJECTIVES: It has become increasingly clear that ATM (ataxia-telangiectasia-mutated) safeguards genome stability, which is a cornerstone of cellular homeostasis, and ATM IVS 22-77 T>C affects the normal activity of ATM proteins. However, the association between the ATM IVS 22-77 T>C genetic variant and cancer risk is controversial. Therefore, we conducted a systematic meta-analysis to estimate the overall cancer risk associated with the polymorphism and to quantify any potential between-study heterogeneity.
METHODS: A total of nine studies including 4,470 cases and 4,862 controls were analyzed for ATM IVS 22-77 T>C association with cancer risk in this meta-analysis. Heterogeneity among articles and their publication bias were also tested.
RESULTS: Our results showed that no association reached the level of statistical significance in the overall risk. Interestingly, in the stratified analyses, we observed an inverse relationship in lung and breast cancer.
CONCLUSION: Further functional research on the ATM mechanism should be performed to explain the inconsistent results in different cancer types.

Shen L, Yin ZH, Wan Y, et al.
Association between ATM polymorphisms and cancer risk: a meta-analysis.
Mol Biol Rep. 2012; 39(5):5719-25 [PubMed] Related Publications
To date, epidemiological studies have assessed the association between Ataxia-telangiectasia mutated (ATM) gene polymorphisms and cancer risk, including lung cancer, breast cancer, glioma and pancreatic cancer. However, the results of these studies remain controversial. We aimed to examine the associations between two SNPs (rs664143 and rs664677) and cancer risk by conducting a meta-analysis of case-control studies. A total of 12 publications were included in this meta-analysis, 8 for rs664143 and 7 for rs664677. Overall, rs664143 heterozygote carriers turned out to be associated with cancer risk (OR = 1.18, 95% CI 1.02-1.36). In the subgroup analysis by cancer type, we observed that the ATM rs664143 polymorphism was significantly associated with lung cancer risk (GA vs. GG: OR = 1.48, 95% CI 1.18-1.85, AA vs. GG: OR = 1.51, 95% CI 1.18-1.93) and rs664677 polymorphism was associated with decreased lung cancr risk and increased breast cancer risk (for lung cancer: TC vs. TT: OR = 0.76, 95% CI 0.62-0.92, CC vs. TT: OR = 0.80, 95% CI 0.64-0.99 and for breast cancer: TC vs. TT: OR = 1.42, 95% CI 1.17-1.73, CC vs. TT: OR = 1.51, 95% CI 1.21-1.87). In the subgroup analysis by region, we also observed that individuals with ATM rs664143 GA or AA genotype had an obvious increased cancer risk among Asian people (GA vs. GG: OR = 1.40, 95% CI 1.20-1.63, AA vs. GG: OR = 1.37, 95% CI 1.16-1.62). In conclusion, ATM rs664143 polymorphism was associated with cancer susceptibility. ATM rs664143 polymorphism was significantly associated with lung cancer risk. ATM rs664677 polymorphism was associated with decreased lung cancer risk as well as increased breast cancer risk.

Sharma A, Bode B, Wenger RH, et al.
γ-Radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo.
PLoS One. 2011; 6(11):e28217 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: γ-radiation is an effective treatment for cancer. There is evidence that radiotherapy supports tumor-specific immunity. It was described that irradiation induces de novo protein synthesis and enhances antigen presentation, we therefore investigated whether γ-radiation results in increased expression of cancer-testis (CT) antigens and MHC-I, thus allowing efficient immunological control. This is relevant because the expression of CT-antigens and MHC-I on tumor cells is often heterogeneous. We found that the changes induced by γ-radiation promote the immunological recognition of the tumor, which is illustrated by the increased infiltration by lymphocytes after radiotherapy.
METHODS/FINDINGS: We compared the expression of CT-antigens and MHC-I in various cancer cell lines and fresh biopsies before and after in vitro irradiation (20 Gy). Furthermore, we compared paired biopsies that were taken before and after radiotherapy from sarcoma patients. To investigate whether the changed expression of CT-antigens and MHC-I is specific for γ-radiation or is part of a generalized stress response, we analyzed the effect of hypoxia, hyperthermia and genotoxic stress on the expression of CT-antigens and MHC-I. In vitro irradiation of cancer cell lines and of fresh tumor biopsies induced a higher or de novo expression of different CT-antigens and a higher expression of MHC-I in a time- and dose-dependent fashion. Importantly, we show that irradiation of cancer cells enhances their recognition by tumor-specific CD8+ T cells. The analysis of paired biopsies taken from a cohort of sarcoma patients before and after radiotherapy confirmed our findings and, in addition showed that irradiation resulted in higher infiltration by lymphocytes. Other forms of stress did not have an impact on the expression of CT-antigens or MHC-I.
CONCLUSIONS: Our findings suggest that γ-radiation promotes the immunological recognition of the tumor. We therefore propose that combining radiotherapy with treatments that support tumor specific immunity may result in increased therapeutic efficacy.

Knobel PA, Kotov IN, Felley-Bosco E, et al.
Inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells.
Neoplasia. 2011; 13(10):961-70 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
REV3 is the catalytic subunit of DNA translesion synthesis polymerase ζ. Inhibition of REV3 expression increases the sensitivity of human cells to a variety of DNA-damaging agents and reduces the formation of resistant cells. Surprisingly, we found that short hairpin RNA-mediated depletion of REV3 per se suppresses colony formation of lung (A549, Calu-3), breast (MCF-7, MDA-MB-231), mesothelioma (IL45 and ZL55), and colon (HCT116 +/-p53) tumor cell lines, whereas control cell lines (AD293, LP9-hTERT) and the normal mesothelial primary culture (SDM104) are less affected. Inhibition of REV3 expression in cancer cells leads to an accumulation of persistent DNA damage as indicated by an increase in phospho-ATM, 53BP1, and phospho-H2AX foci formation, subsequently leading to the activation of the ATM-dependent DNA damage response cascade. REV3 depletion in p53-proficient cancer cell lines results in a G(1) arrest and induction of senescence as indicated by the accumulation of p21 and an increase in senescence-associated β-galactosidase activity. In contrast, inhibition of REV3 expression in p53-deficient cells results in growth inhibition and a G(2)/M arrest. A small fraction of the p53-deficient cancer cells can overcome the G(2)/M arrest, which results in mitotic slippage and aneuploidy. Our findings reveal that REV3 depletion per se suppresses growth of cancer cell lines from different origin, whereas control cell lines and a mesothelial primary culture were less affected. Thus, our findings indicate that depletion of REV3 not only can amend cisplatin-based cancer therapy but also can be applied for susceptible cancers as a potential monotherapy.

Berdelle N, Nikolova T, Quiros S, et al.
Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells.
Mol Cancer Ther. 2011; 10(12):2224-33 [PubMed] Related Publications
Artesunate, the active agent from Artemisia annua L. used in the traditional Chinese medicine, is being applied as a first-line drug for malaria treatment, and trials are ongoing that include this drug in cancer therapy. Despite increasing interest in its therapeutic application, the mode of cell killing provoked by artesunate in human cells is unknown. Here, we show that artesunate is a powerful inducer of oxidative DNA damage, giving rise to formamidopyrimidine DNA glycosylase-sensitive sites and the formation of 8-oxoguanine and 1,N6-ethenoadenine. Oxidative DNA damage was induced in LN-229 human glioblastoma cells dose dependently and was paralleled by cell death executed by apoptosis and necrosis, which could be attenuated by radical scavengers such as N-acetyl cysteine. Oxidative DNA damage resulted in DNA double-strand breaks (DSB) as determined by γH2AX foci that colocalized with 53BP1. Upon chronic treatment with artesunate, the level of DSB continuously increased over the treatment period up to a steady-state level, which is in contrast to ionizing radiation that induced a burst of DSB followed by a decline due to their repair. Knockdown of Rad51 by short interfering RNA and inactivation of DNA-PK strongly sensitized glioma cells to artesunate. These data indicate that both homologous recombination and nonhomologous end joining are involved in the repair of artesunate-induced DSB. Artesunate provoked a DNA damage response (DDR) with phosphorylation of ATM, ATR, Chk1, and Chk2. Overall, these data revealed that artesunate induces oxidative DNA lesions and DSB that continuously increase during the treatment period and accumulate until they trigger DDR and finally tumor cell death.

Janssen A, van der Burg M, Szuhai K, et al.
Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations.
Science. 2011; 333(6051):1895-8 [PubMed] Related Publications
Various types of chromosomal aberrations, including numerical (aneuploidy) and structural (e.g., translocations, deletions), are commonly found in human tumors and are linked to tumorigenesis. Aneuploidy is a direct consequence of chromosome segregation errors in mitosis, whereas structural aberrations are caused by improperly repaired DNA breaks. Here, we demonstrate that chromosome segregation errors can also result in structural chromosome aberrations. Chromosomes that missegregate are frequently damaged during cytokinesis, triggering a DNA double-strand break response in the respective daughter cells involving ATM, Chk2, and p53. We show that these double-strand breaks can lead to unbalanced translocations in the daughter cells. Our data show that segregation errors can cause translocations and provide insights into the role of whole-chromosome instability in tumorigenesis.

Wang J, Su F, Smilenov LB, et al.
Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity.
Radiat Oncol. 2011; 6:96 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that Atm/Brca1 double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet. In the present study, a series of pathways were investigated to clarify the possible mechanisms of increased risk of tumorigenesis in Atm and Brca1 heterozygosity.
METHODS: Wild type cells, Atm or Brca1 single heterozygous cells, and Atm/Brca1 double heterozygous cells were used to investigate DNA damage and repair, cell cycle, micronuclei, and cell transformation after photon irradiation.
RESULTS: Remarkable high transformation frequency was confirmed in Atm/Brca1 double heterozygous cells compared to wild type cells. It was observed that delayed DNA damage recognition, disturbed cell cycle checkpoint, incomplete DNA repair, and increased genomic instability were involved in the biological networks. Haploinsufficiency of either ATM or BRCA1 negatively impacts these pathways.
CONCLUSIONS: The quantity of critical proteins such as ATM and BRCA1 plays an important role in determination of the fate of cells exposed to ionizing radiation and double heterozygosity increases the risk of tumorigenesis. These findings also benefit understanding of the individual susceptibility to tumor initiation.

Kumar A, Rai PS, Upadhya R, et al.
γ-radiation induces cellular sensitivity and aberrant methylation in human tumor cell lines.
Int J Radiat Biol. 2011; 87(11):1086-96 [PubMed] Related Publications
PURPOSE: Ionizing radiation induces cellular damage through both direct and indirect mechanisms, which may include effects from epigenetic changes. The purpose of this study was to determine the effect of ionizing radiation on DNA methylation patterns that may be associated with altered gene expression.
MATERIALS AND METHODS: Sixteen human tumor cell lines originating from various cancers were initially tested for radiation sensitivity by irradiating them with γ-radiation in vitro and subsequently, radiation sensitive and resistant cell lines were treated with different doses of a demethylating agent, 5-Aza-2'-Deoxycytidine (5-aza-dC) and a chromatin modifier, Trichostatin-A (TSA). Survival of these cell lines was measured using 3-(4, 5-Dimethylthiazol- 2-yl)-2, 5-diphenyltetrazolium (MTT) and clonogenic assays. The effect of radiation on global DNA methylation was measured using reverse phase high performance liquid chromatography (RP-HPLC). The transcription response of methylated gene promoters, from cyclin-dependent kinase inhibitor 2A (p16(INK4a)) and ataxia telangiectasia mutated (ATM) genes, to radiation was measured using a luciferase reporter assay.
RESULTS: γ-radiation resistant (SiHa and MDAMB453) and sensitive (SaOS2 and WM115) tumor cell lines were examined for the relationship between radiation sensitivity and DNA methylation. Treatment of cells with 5-aza-dC and TSA prior to irradiation enhanced DNA strand breaks, G2/M phase arrest, apoptosis and cell death. Exposure to γ-radiation led to global demethylation in a time-dependent manner in tumor cells in relation to resistance and sensitivity to radiation with concomitant activation of p16(INK4a) and ATM gene promoters.
CONCLUSION: These results provide important information on alterations in DNA methylation as one of the determinants of radiation effects, which may be associated with altered gene expression. Our results may help in delineating the mechanisms of radiation resistance in tumor cells, which can influence diagnosis, prognosis and eventually therapy for human cancers.

Zoppoli G, Solier S, Reinhold WC, et al.
CHEK2 genomic and proteomic analyses reveal genetic inactivation or endogenous activation across the 60 cell lines of the US National Cancer Institute.
Oncogene. 2012; 31(4):403-18 [PubMed] Related Publications
CHEK2 encodes a serine/threonine kinase (Chk2) activated by ATM in response to DNA double-strand breaks. On the one hand, CHEK2 has been described as a tumor suppressor with proapoptotic, cell-cycle checkpoint and mitotic functions. On the other hand, Chk2 is also commonly activated (phosphorylated at T68) in cancers and precancerous lesions. Here, we report an extensive characterization of CHEK2 across the panel of 60 established cancer cell lines from the NCI Anticancer Screen (the NCI-60) using genomic and proteomic analyses, including exon-specific mRNA expression, DNA copy-number variation (CNV) by aCGH, exome sequencing, as well as western blot analyses for total and activated (pT68-Chk2) Chk2. We show that the high heterogeneity of Chk2 levels in cancer cells is primarily due to its inactivation (owing to low gene expression, alternative splicing, point mutations, copy-number alterations and premature truncation) or reduction of protein levels. Moreover, we observe that a significant percentage of cancer cells (12% of the NCI-60 and HeLa cells) show high endogenous Chk2 activation, which is always associated with p53 inactivation, and which is accompanied by downregulation of the Fanconi anemia and homologous recombination pathways. We also report the presence of activated Chk2 (pT68-Chk2) along with histone γ-H2AX in centrosomes.

Levy A, Albiges-Sauvin L, Massard C, et al.
[Cell cycle, mitosis and therapeutic applications].
Bull Cancer. 2011; 98(9):1037-45 [PubMed] Related Publications
Genomic DNA is constantly under stress of endogenous and exogenous DNA damaging agents. Without proper care, the DNA damage causes an alteration of the genomic structure and can lead to cell death or the occurrence of mutations involved in tumorigenesis. During the process of evolution, organisms have acquired a series of response mechanisms and repair of DNA damage, thereby ensuring the maintenance of genome stability and faithful transmission of genetic information. The checkpoints are the major mechanisms by which a cell can respond to DNA damage, either by actively stopping the cell cycle or by induction of apoptosis. Two parallel signalling pathways, ATM and ATR respond to genotoxic stress by activating their downstream target proteins including the two effectors kinases CHK1 and CHK2. Promising preliminary data render these proteins potential targets for therapeutic development against cancer.

Fraser M, Harding SM, Zhao H, et al.
MRE11 promotes AKT phosphorylation in direct response to DNA double-strand breaks.
Cell Cycle. 2011; 10(13):2218-32 [PubMed] Related Publications
AKT is hyper-activated in many human cancers and promotes proliferation and cancer cell survival in response to DNA damaging agents. Ionizing radiation (IR) produces DNA double strand breaks (DSB) and activates AKT, however a direct mechanism linking intra-nuclear DSB and AKT signaling is lacking. Here we demonstrate that AKT is phosphorylated following IR in benign and malignant cells and, using colony-forming assays and in vitro rejoining assays, show that AKT promotes non-homologous end joining-mediated DSB repair and cell survival following IR. Further studies revealed that pAKT-S473, but not pAKT-T308 or total AKT, accumulates in the vicinity of IR-induced DSB and co-localizes with γH2AX and ATM-pSer1981. Based on whole-cell IR, nuclear UV microbeam, and endonuclease-induced DSB studies, we observed that pAKT-S473 is up-regulated by a DSB-induced signaling cascade, and this is dependent on the DSB sensor protein, MRE11. MRE11-dependent pAKT-S473 did not require the MRE11 endonuclease domain. The histone ubiquitin ligase RNF168 is also required for DSB-induced pAKT-S473, and DSB-induced pAKT-S473 is independent of DNA-PKcs, PI3K, and ATR. These data demonstrate that DSB activate a signaling cascade that directly promotes a PI3K-independent pathway of AKT phosphorylation that is dependent on MRE11-ATM-RNF168 signaling. Thus, these data directly link the presence of DNA breaks to AKT-mediated cell survival and support AKT as a target for cancer therapy.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. ATM, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 18 March, 2015     Cancer Genetics Web, Established 1999