Oncogene (2014) 33, 3351–3360 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc

REVIEW ATM signalling and cancer

CA Cremona and A Behrens

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.

Oncogene (2014) 33, 3351–3360; doi:10.1038/onc.2013.275; published online 15 July 2013 Keywords: ATM; signalling; cancer

INTRODUCTION TRRAP proteins) and FATC domains at the C terminus, the protein ATM, the gene mutated in ataxia telangiectasia (A-T), has been also contains N-terminal HEAT repeats (named after the proteins associated with cancer since its discovery, because A-T patients huntingtin, elongation factor 3, the A subunit of PP2A and TOR1) are prone to thymic lymphoma and other cancers.1 The first and a substrate-binding domain. The kinase domain is responsible explanation for this predisposition was that ATM encodes a kinase for several autophosphorylations, as well as phosphorylating the 3 central to the repair of double-strand breaks (DSBs) in DNA, hundreds of ATM substrates identified so far. The high number of thereby controlling genome stability and cell survival (reviewed in targets and extensive potential for modulation places ATM as a Shiloh2). A-T cells show radioresistant DNA synthesis—failure to signalling hub, with many different inputs and a complex output stop or slow cell-cycle progression in response to radiation subject to the actions of cofactors, substrates and feedback damage—revealing a lack of checkpoint control that clearly regulation. contributes to cancer predisposition. However, this is just one aspect of ATM’s function. Over recent years, a wealth of evidence has accumulated showing that ATM is part of many other ATM SIGNALLING signalling networks, including cell metabolism and growth, ATM signalling can be broadly divided into two categories: a oxidative stress, and chromatin remodelling, all of which can canonical pathway, which signals together with the Mre11-Rad50- affect cancer progression. These diverse effects mean that the NBS1 (MRN) complex from DSBs and activates the DNA damage predisposition to cancer of various types, and its clinical course in checkpoint, and several non-canonical modes of activation, which each case, is altered by inherited and spontaneous ATM mutations. are activated by other forms of cellular stress (Figure 2). Both Although ATM is rightly considered to be a tumour suppressor, signalling categories are likely to contribute to ATM’s role in ATM signalling can also be advantageous to cancer cells, tumour suppression. particularly in resistance to radio- and chemotherapeutic treat- ment. For this reason, ATM inhibitors have been developed for use Canonical ATM signalling at DSBs in cancer therapy. Here we will review these apparently ATM kinase is present in its inactive form as a non-covalently paradoxical ATM functions with reference to ATM signalling in 4 cancer cell and mouse models as well as human patients. linked dimer. Canonical ATM activation, in response to DSBs, involves dimer dissociation, activation of monomers and recruitment to DNA break sites. The MRN complex is required ATM—a multifunctional kinase for ATM recruitment to DSBs and efficient activation: the NBS1 The ATM protein is a very large, 370 kDa kinase encoded on subunit interacts directly with ATM, and ubiquitination of NBS1 human chromosome 11q22-23. Mouse ATM, encoded on chromo- helps ATM recruitment.5–7 The end clipping activity of MRN also some 9, is 84% identical to the human protein, and homologs contributes to ATM activation by generating short ssDNA oligos have been found in all eukaryotes. Because of its size, a detailed that associate with it.8 Ionising radiation (IR)-induced ATM atomic structure of the whole protein has not yet been activation via MRN results in the phosphorylation of a vast determined, but a combination of extensive mapping of patient network of substrates, including the key checkpoint kinase Chk2 mutations, in vitro studies and comparison with related phospha- and the tumour suppressor p53 (Figure 2). tidylinositol-like superfamily proteins has resulted in a well- ATM autophosphorylation at serine 1981 (Ser1981; equivalent defined domain structure incorporating many post-translational to Ser1987 in mice) occurs within 1 min of irradiation and is widely modification sites (Figure 1). As well as a PI3K-like serine/threonine used as a read-out of ATM activation.4,9 However, in the absence kinase, which is flanked by FAT (named after the FRAP, ATR and of MRN, ATM monomers are not phosphorylated at Ser1981 but

Mammalian Genetics Lab, Cancer Research UK London Research Institute, London, UK. Correspondence: Dr A Behrens, Mammalian Genetics Lab, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK. E-mail: [email protected] Received 26 March 2013; revised 17 May 2013; accepted 20 May 2013; published online 15 July 2013 ATM and cancer CA Cremona and A Behrens 3352 HEAT repeats

P P P P P Cys P Chromatin binding Substrate binding NLS Caspase 3 sites Leucine zipper NBS1 binding FAT PI3K FATC

ATM N C 3056 a.a.

367 794 1403 1893 1981 2996 Figure 1. Domain structure of human ATM. ATM can be divided into an N-terminal half that is largely unique, and a C-terminal half that has homology to other phosphoinositide-3 kinase (PI3K)-like kinases such as ATR, mTOR and DNA-PKcs. This conserved portion contains a FAT domain (named after the FRAP, ATR, and TRRAP proteins), the PI3K-like serine/threonine kinase domain (here shown in red), and a FAT C-terminal domain (FATC). ATM contains at least five autophosphorylation sites: serines 367, 1893, 1981 and 2996, whose phosphorylation is induced after IR; and threonine 1885, which is not induced by IR.189 Cdk5 phosphorylates serine 794 in postmitotic neurons,190 and Aurora B phosphorylates serine 1403 in mitosis.191 In oxidising conditions, cysteine 2991 forms a disulphide linkage with a second ATM molecule to form a dimer.68 The N-terminal portion interacts with substrates and cofactors such as NBS1, p53, BRCA1, LKB1 and BLM; amino acids 91–97 (here shown in purple) are required for IR-induced formation of nuclear ATM foci.192 Also in the N-terminal portion are a proposed chromatin- interaction domain, a nuclear localisation sequence (NLS), two caspase 3 cleavage sites, and a putative leucine zipper region.193–195 The majority of the protein is composed of 49 HEAT repeats (named after the proteins huntingtin, elongation factor 3, the A subunit of PP2A and TOR1).196 These likely mean that ATM is highly flexible; indeed, a low-resolution structural study of ATM found a flexible arm region that changes conformation upon DNA binding.197 Diagram produced using Domain Graph 2.0.198

17–19 Canonical Non-canonical Redox damage sites. RNF168 monoubiquitylates histones H2A and Ionising Chromatin changes H2AX on lysines 13 and 15 and primes them for polyubiquity- radiation (hypotonic stress; chloroquine) Oxidation lation, necessary for recruitment of further repair factors.20 ATM and Mdc1 determine the spreading of gH2AX along chromatin, while ubiquitin enzymes control spreading of ubiquitylated histones.21,22 Continued ATM activation is required to maintain ATMATM ATM ATM ATM ATM damage foci even when ubiquitylated regions are expanded.22 A complex feedback system dynamically tunes ATM signalling to the existing damage—as long as damage persists above a threshold, ATM is activated in a pulse-like manner due to feedback 23 P P P P from activated p53. The molecular details of ATM signalling 24–26 ATM NBS1 ATM ATMIN ATM ATM at DSBs have been extensively reviewed. Here we will highlight the emerging interplay between ATM and chromatin in this response. Many groups have shown that ATM is important for the repair of DSBs at diverse genome locations, including euchromatic P P P P P 15,27,28 Chk2 Chk2 Chk2 Smc1 Smc1 immunoglobulin loci, while others have found that it is particularly required for DSBs located in heterochromatin.29,30 P P P Kap1 Kap1 ? Although experiments with laser lines show a local P P P 9 p53 p53 p53 decondensation of chromatin at DSBs that is ATM-independent, P ATM also decondenses chromatin to increase accessibility to ? • DSB repair repair machinery and reinforce its own activation. ATM-dependent • Cell cycle arrest • Genome stability phosphorylation of RNF20/RNF40 leads to ubiquitination of • Radiosensitivity • Control of cell survival • Oxidative stress response histone H2B, and ATM phosphorylation of Kap1 reduces its affinity for the chromodomain protein CHD3, both of which lead Figure 2. Canonical and non-canonical ATM signalling pathways. 31–33 ATM signals together with the MRN complex at DSBs (canonical to decompaction of chromatin structure. pathway, left); together with ATMIN following non-DSB stimuli such Chromatin relaxation at DSB sites also ensures efficient ATM as oxidative stress and chromatin changes (middle) and can also activation. It has long been known that histone deacetylase form disulphide dimers in oxidative stress conditions (right). inhibitors activate ATM,4 and Tip60 mediates acetylation of Chromatin remodelling around DSBs also contributes to canonical histones H4 and H2AX to remodel chromatin at DSB sites.34 ATM activation. The MRN subunit NBS1 and ATMIN bind competi- 47 DMAP1, a member of the Tip60 histone acetyltransferase complex, tively to ATM, but the relationship between the redox dimer and is required for H4K16 acetylation and ATM activation in response the other pathways is unknown. For simplicity, only a subset of key to DNA damage.35 The nucleosome-binding protein HMGN1 ATM substrates is shown. See text for details. increases H3K14 acetylation, also loosening chromatin structure. This allows a threefold increase in chromatin-bound ATM in response to DSBs.36 Activation of ATM in response to UV damage can still phosphorylate the histone H2AX in response to DSBs.10 is also enhanced by chromatin decompaction: the NER protein This argues that autophosphorylation is separable from ATM XPC recruits the chromatin remodelling complex SWI/SNF, which dimer dissociation and activity in some situations. In support of in turn increases ATM recruitment.37 this idea, ATM mutants lacking autophosphorylation sites are Conversely, ATM also mediates transcriptional silencing, asso- functional,11,12 though phosphorylation at Ser1981 may be ciated with chromatin compaction, at chromosome regions necessary for retention of ATM at DSB sites.13–15 spreading several kilobases from a DSB.38,39 Histone H2A K119 Activated ATM phosphorylates H2AX, enabling the recruitment monoubiquitination, required for silencing, is partly ATM of DNA repair complexes visible by immunofluorescence as dependent and occurs via the E3 ubiquitin ligase Bmi1.39–41 nuclear foci.16 ATM-dependent phosphorylation of Mdc1 also RNF168-mediated ubiquitylation of histone H2A K13-15 also recruits RNF8 and consequently RNF168 ubiquitin ligases to affects the extent of silencing.22 This mechanism is likely to be

Oncogene (2014) 3351 – 3360 & 2014 Macmillan Publishers Limited ATM and cancer CA Cremona and A Behrens 3353 relevant mainly in euchromatic regions, and so would not conflict machinery in S phase.56,57 However, if DSBs were the sole trigger, with ATM-mediated opening of heterochromatin.42 A similar we would expect more ATM activation in ATR-deficient cells due to silencing process involving the related kinase ATR (ATM and increased fork collapse and DSB formation, yet ATM signalling after Rad3-related) occurs during spermatogenesis.43 UV is reduced.55 It is therefore likely that some ATM signalling occurs specifically in response to replication stress and ATR activation and is not just stimulated by DSBs. Non-canonical ATM signalling Currently, however, it is unclear exactly what triggers ATM ATM signalling via ATMIN. Interestingly, ATM is also activated by signalling in replication stress conditions. Replication stress induced chromatin changes alone, in the absence of detectable DNA by DNA interstrand crosslinks activates ATM via the WRN helicase,58 damage. Cell culture treatments such as chloroquine and and ATM-dependent phosphorylation of WRN is important for the hypotonic stress activate ATM and cause phosphorylation of recovery of collapsed replication forks. Interestingly, relocalisation downstream targets, such as p53 and Kap1.4 Importantly, NBS1 is 44 of WRN into nuclear foci following replication stress requires not required for ATM activation by these stimuli, suggesting that phosphorylation by ATR,59 supporting the idea that ATR may be a there is a second, non-canonical pathway of ATM activation. prerequisite for ATM activation at stalled forks. ATMIN (also called ASCIZ) was identified as an ATM substrate and 45 Other forms of replication stress have been shown to activate modulator of DNA repair and subsequently revealed as an ATM ATM independently of ATR. For example, nuclear bodies containing interactor required for ATM signalling in response to chloroquine 46 53BP1 form at some fragile sites after replication, in an ATM- and hypotonic stress (Figure 2). Recent work has shown that dependent manner that does not require ATR.60 ATM is required for ATMIN binds to ATM using a motif homologous to the ATM replication-coupled repair and viability following thymidine block, interaction motif of NBS1 and that ATMIN competes with NBS1 for 47 and phosphorylation of ATM is required for Ras-induced replicative ATM. ATMIN is not required for IR-induced ATM signalling, and senescence.61,62 Oncogene-induced stress was reported to induce a physiologically relevant stimuli triggering ATM signalling via limited ATM checkpoint response, insufficient to prevent progress ATMIN are still elusive. However, phosphorylation of ATM targets into M phase.63 in response to reactive oxygen species (ROS) partly requires Recently, ATM has been found to interact with proliferating cell ATMIN, and ATMIN-deficient murine embryonic fibroblasts (MEFs) 48 nuclear antigen and stimulate DNA Pol delta activity in untreated are more sensitive to atmospheric oxygen than wild-type MEFs. cells, possibly facilitating replication associated with homologous recombination or gap repair.64 Importantly, this function of ATM ATMIN signalling in genome stability and cancer. The importance was only revealed with the use of an ATM inhibitor, and not in cells of ATMIN for genome stability is demonstrated by the aberrant depleted of ATM, though the reason for this discrepancy is not chromosomal translocations and lymphoma development seen in yet clear. mice with ATMIN-deficient B cells.49 ATMIN-deficient B cells contain aberrant translocations similar to those in ATM-deficient ATM at telomeres. Chromosome ends normally exist within cells, and ATMIN deficiency does not further impair class switch specialised telomere structures consisting of looped DNA and a recombination in cells treated with ATM inhibitor, suggesting that protein complex, shelterin, to prevent them from being recog- the ATMIN-null phenotype occurs, at least in part, through nised as DSBs. DNA damage response proteins such as ATM are defective ATM signalling. Unusually, correct recombination of recruited to telomeres but are inhibited by the shelterin immunoglobulin genes following DSB induction requires both complex.65 The shelterin subunit TRF2 inhibits ATM in two ways: ATMIN and NBS1, indicating that both canonical and non- by directly inhibiting its activation, and by inhibiting the canonical ATM signalling is required. propagation of the ATM signal.66 Telomere dysfunction, either The timing of ATMIN deletion is important: B-cell lymphomas from lack of ATM or from inappropriate ATM activation at develop when the CD19-cre line is used but not when ATMIN is uncapped telomeres, results in chromosome fusions and hence deleted earlier in haematopoietic stem cells using the Vav2 genome instability, increasing the scope for malignancy.67 promoter (Loizou et al.49 and unpublished data). Consistent with this, Heierhorst and colleagues used Mb-1-cre to delete ATMIN ATM as a redox sensor. A separate pathway of ATM activation from the early pro-B-cell stage and found B-cell lymphopenia but occurs through dimer oxidation. Instead of dissociating, disulphide no lymphomas. This earlier defect was caused by impaired cell bonds form between cysteine residues, resulting in an active 50 survival due to aberrant transcriptional regulation of Dynll1. dimeric form capable of phosphorylating a subset of ATM 48,51 The ATMIN-null mouse is embryonic lethal, though it is substrates. Oxidation results from exposure to atmospheric levels not known whether aberrant transcription contributes to this of oxygen, or ROS such as those produced by hydrogen peroxide, phenotype. At present, it is unclear how the transcriptional role of and activates ATM directly without the need for MRN68 (Figure 2). ATMIN integrates with ATM signalling. The C2991L point mutant of ATM, which is unable to form the disulphide dimer, is able to respond to DNA damage but not to ATM signalling in replication stress and cross-talk with ATR.The ROS.68 The activated ATM dimer is also phosphorylated at DNA damage response from replication stress and excess single- Ser1981, but as with the monomer, this modification is not stranded DNA is mainly associated with the ATR kinase, not ATM. required for phosphorylation of downstream substrates, including In certain instances, however, the ATM and ATR arms of the DNA p53 Ser18 (Ser15 in mice) and Chk2 Thr68.68 damage response are linked. For example, at DSBs, ATM-dependent ROS-activated ATM activates TSC2 via phosphorylation of LKB1 extensive resection of the 50 strand exposes single-stranded DNA and AMPK, and this inhibits mTORC (mammalian target of that induces activation of ATR, and there is a clear switch between rapamycin complex) signalling, thereby decreasing ROS levels.69 the two kinases depending on the length of the overhang.52 Thus ATM is a redox regulator that reduces oxidative stress. In Conversely, some ATM signalling depends on previous activation support of this, ATM-deficient mice show elevated ROS, and A-T of ATR. For example, treatment of cells with IR induces ATR- cells are more prone to apoptosis when exposed to further dependent ATM phosphorylation in neighbouring ‘bystander’ cells oxidative stress.70,71 Disregulated redox signalling is an important that receive soluble distress signals.53 UV irradiation induces contributor to the A-T phenotype: lymphoma development in replication fork stalling and ATR-dependent activation of ATM.54,55 ATM-deficient mice is precipitated by elevated ROS and can be More recent studies have suggested that ATM activation following rescued by administering antioxidants.70 Similarly, decreased ATM replication fork stalling is due to replication fork collapse and DSB function is associated with insulin resistance72 and antioxidants formation, when lesions are encountered by the replication can rescue this phenotype,73 arguing that increased ROS, as well

& 2014 Macmillan Publishers Limited Oncogene (2014) 3351 – 3360 ATM and cancer CA Cremona and A Behrens 3354 as the decreased phosphorylation of ATM targets such as Akt removing ATM completely: deletion of NBS1 is also lethal in Ser473 and p53 Ser18, contributes to metabolic stress in ATM- MEFs, but cell viability is restored by concomitant deletion of deficient animals. ATMIN.47 Interestingly, the ATM kinase-dead mouse is also Cementing its position as a redox sensor, ATM is also activated embryonic lethal,92,93 indicating that inactive ATM is deleterious by hypoxia independently of ROS.74 Hypoxia induces ATM during embryogenesis. Conceivably, the ATM kinase-dead and phosphorylation of the transcription factor HIF1 alpha, which ATMIN-null embryonic lethal phenotypes could be related (if, for stabilises the protein and leads to inhibition of mTORC1 signalling example, both result in inappropriately localised ATM protein), but via REDD1.75 This activation of ATM occurs in a diffuse manner in at present there is no evidence to link these two phenotypes. the nucleus, independently of DSB formation.74,75 It is unclear The reason for the lethality of kinase-dead ATM is not yet whether the active ATM in this case is the oxidised disulphide understood, particularly because both initial studies indicated that dimer described by Guo et al.,68 or a different form. Interestingly, a the inactive protein is not a classical dominant negative,92,93 and diffuse pattern of nuclear phospho-ATM staining is also seen in its effect on tumourigenesis remains to be explored. However, the p16- or p21-induced cellular senescence.76 Prolonged ATM notion that mutant ATM can be worse than no ATM is supported signalling via Chk2 is required for the production of senescence- by the increased tumour development in mice heterozygous for associated secretory phenotype cytokines, which in turn boost the the human 7636del9 ATM mutation (7636del9/ þ ) compared with DNA damage response.77,78 It is thus possible that redox activation germline ATM þ / À heterozygotes94 and increased genome of ATM may enhance the response to other forms of damage. instability in ATM kinase-dead/ À heterozygotes compared with Because conditions in solid tumours involve both hypoxia and ATM null cells.93 elevated ROS, ATM signalling may in fact reduce oxidative stress ATM also shows haploinsufficiency in tumour suppression: and promote cell survival in some tumours, in addition to its well- ATM heterozygosity increases the incidence of mammary carci- documented tumour-suppressive function in promoting genome nomas in TP53 heterozygote mice.95 p53 deficiency accelerates stability. tumourigenesis in ATM-null mice, as well as expanding the type of malignancies to sarcomas and B-cell as well as T-cell ATM and transcription. Activation of ATM leads to an extensive lymphomas.96 The p53 Ser18Ala mutation shows some embryonic programme of transcriptional changes, many of which rely on the lethality in combination with ATM deficiency, and the remaining stabilisation and activation of p53.79 As well as this nuclear mice develop T-cell lymphomas.97 pathway, ATM also activates transcription through a pathway Cdc20 deficiency accelerates thymic lymphomagenesis in ATM- involving nuclear-cytoplasmic shuttling and nuclear factor (NF)-kB. null mice,98 whereas p21 and WIP1 deficiencies delay it.99,100 In response to IR, ATM phosphorylates NEMO and shuttles to the Interestingly, RNF8/Chfr double knockout mice, which lack the cytoplasm to activate inhibitor-kB kinase and hence NF-kB.80 At ubiquitin ligases that control chromatin relaxation via H4K16 the same time, ATM promotes NF-kB activation via ubiquitylation acetylation, develop thymic lymphomas similar to ATM-null mice, of NEMO and ELKS.81,82 NEMO sumoylation also promotes NF-kB suggesting a similar defect in DSB repair.101 activation, and a negative feedback loop involving ATM- In the absence of ATM, mice become more reliant on other dependent expression of the SUMO protease SENP2 leads to repair proteins: ATM/PARP1 (poly ADP-ribose polymerase 1) and desumoylation and inhibition of NF-kB signalling.83,84 ATM/H2AX double knockout mice are embryonic lethal.102,103 This Interestingly, the outcome of NF-kB signalling appears to be synthetic lethality could be exploited for cancer therapy, either by different depending on the type of stress encountered. Wu and inhibiting repair in ATM-deficient cells or by combining ATM Miyamoto85 found that replication stress tended to promote inhibitors with other DNA-damaging agents. This will be discussed apoptosis, whereas signalling induced by DSBs favoured cell further under ‘ATM signalling in human cancer and therapy’. survival, despite both stimuli using an ATM-dependent pathway for NF-kB activation. It is possible that different forms of ATM may be involved depending on the stimulus; at present, it is unclear ATM SIGNALLING IN CANCER CELLS whether NF-kB signalling is activated by an autophosphorylated The main tumour-suppressive effects of ATM signalling in cancer ATM monomer as in the canonical signalling pathway, the cells are the induction of cell-cycle arrest and apoptosis. ATM disulphide-linked oxidised dimer, or another ATM active form. phosphorylates human DBC1 (deleted in breast cancer) and promotes apoptosis via SIRT1 and p53.104 ATM also phosphorylates PIDD and promotes apoptosis via RAIDD binding ATM-DEFICIENT MOUSE MODELS and activation of caspase 2.105 ATM and Chk1-dependent cell- ATM’s response to cellular stresses such as DNA damage and ROS cycle arrest and apoptosis can be induced by curcumin in acts to limit the proliferation of aberrant cells and protect cells pancreatic cancer cells.106 Other agents such as the antibiotic from conditions that can lead to tumourigenesis. ATM-null mice Asperlin and the proteasome inhibitor bortezomib induce cell- develop T-cell lymphomas with high penetrance due to defective cycle arrest by activating ATM in a ROS-dependent manner.107,108 V(D)J recombination,86–89 and loss of ATM doubles the incidence To escape from these effects of ATM activation, cancer cells can of intestinal tumours in APC mutants.90 Notably, although downregulate ATM expression. For example, the microRNA miR- patients with mutations in NBS1 frequently develop lymphoid 18a downregulates ATM expression and is itself upregulated in malignancies, NBS1-deficient mice, or mice expressing a breast cancer.109 Cells may also reduce ATM activity by humanised mutant NBS1 allele found in Nijmegen breakage upregulating WIP1 phosphatase, which dephosphorylates ATM syndrome patients, do not.44,91 This suggests that NBS1 is not and its substrates, such as p53.110 Knockdown of WIP1 restores required for ATM’s tumour-suppressive function in mice. cisplatin sensitivity in oral cancer cells,111 indicating that ATM The development of B-cell lymphomas in conditional ATMIN- signalling can promote cell death in response to chemotherapy. deficient mouse models points towards a tumour-suppressive role Perhaps surprisingly, ATM signalling is more frequently for non-canonical ATM signalling, but the lethality of the ATMIN- upregulated than downregulated in some cancer cells, presum- null mouse means that more conditional models will be needed to ably in those that have already evaded cell-cycle arrest and investigate this role further. As ATM-null mice are viable, it is apoptosis by other means. For example, melanoma cells enhance possible that the embryonic lethal phenotype of ATMIN-deficient ATM signalling by overexpression of MAGE-C2, which binds mice reflects an ATM-independent function of ATMIN. Alterna- to Kap1 and increases its phosphorylation at Ser824.112 tively, disrupting the balance between ATMIN- and NBS1- Prostate cancer cells increase ATM expression by recruiting dependent ATM signalling may be more deleterious than Ack1-phosphorylated androgen receptor to the ATM gene

Oncogene (2014) 3351 – 3360 & 2014 Macmillan Publishers Limited ATM and cancer CA Cremona and A Behrens 3355 enhancer,113 and pancreatic cancer cells overexpress the The increased incidence of breast cancer in families of those with transcription factor CUX1, which increases ATM expression.114,115 A-T has been known for 25 years,140 but the full picture of Another explanation for increased ATM signalling in tumours mutations responsible and their incidence and penetrance is only could be that oncogene activation in precancerous lesions causes now emerging. A-T patients with no detectable ATM kinase replication stress, which activates the DNA damage response, activity almost all develop lymphomas in childhood, while those including ATM, as a barrier to tumourigenesis, and thus ATM with residual kinase activity survive longer but have a 30-fold signalling may remain active in malignant tumours once it has increased rate of breast cancer.141 Patients with Nijmegen been uncoupled from cell-cycle arrest and apoptosis.116–118 breakage syndrome, who have mutations in the MRN subunit The benefits of ATM signalling for cancer cells include promotion NBS1, also have defective ATM activation and are predisposed to of chemoresistance, radioresistance, metastasis and cell survival. cancer, while mutations in the MRN subunit Mre11 cause the rare Chemoresistance may arise from ATM signalling via increased A-T-like disorder, with a similar genome instability phenotype to expression of the crosslinking enzyme transglutaminase 2,119 A-T but no clear cancer predisposition.142,143 activation of p38 MAPK120 or overexpression of HMGA proteins, Heterozygous ATM mutations, which may be present in as many which themselves transcriptionally activate ATM expression.121 as 1% of the population, are associated with a fivefold higher risk Radioresistance, as seen in a subpopulation of breast cancer of breast cancer in those under 50 years of age.144 The known ATM cells,122 simply reflects the increased capacity to deal with DSBs in mutations responsible for the increased susceptibility to breast cells with upregulated ATM signalling. As many chemotherapeutic cancer have been described and catalogued.145,146 Some of these drugs act by inducing DSBs, radioresistant cells are also are highly penetrant; for example, the germline ATM missense frequently resistant to chemotherapy. ATM signalling promotes mutation 7271 T-G has a penetrance similar to BRCA2 mutations metastasis through NF-kB-mediated secretion of protumourigenic with regard to breast cancer.147 In addition to breast cancer, ATM cytokines, which induce an epithelial–mesenchymal transition was recently implicated as a susceptibility gene in a case of (EMT) and promote invasive behaviour.123 Activation of Akt by familial pancreatic ductal adenocarcinoma, with a heterozygous ATM also promotes cell survival in certain contexts.124 Other germline mutation coupled with loss of heterozygosity in the oncogenic effects of ATM signalling include the upregulation of tumour.148 integrin alphavbeta3, which impairs the immune response to the 125 tumour. Somatic ATM mutations in tumours. ATM-inactivating mutations, In other cases, increased ATM signalling has been correlated deletions and expression changes have also been found in with metastatic and invasive behaviour in cancer cells over- tumours themselves (Table 1). ATM point mutations or deletions 126 expressing HOXB9 (40% of breast cancers ) or underexpressing are the most common anomalies found in chronic lymphocytic 127,128 HtrA1 (PRSS11), both associated with EMT-like changes. leukaemia patients at presentation (approximately 25%) and are Increased ATM expression is also associated with metastasis and associated with poor outcome.149,150 Of those patients, 36% have 129 decreased patient survival in neuroendocrine cancer. Although mutations in the remaining ATM allele. The combination of 11q not directly linked to metastasis in these cases, hyperactive ATM deletion and ATM mutation is associated with significantly shorter increases the damage response and therefore promotes chemo- progression-free and overall survival of chronic lymphocytic and radioresistance in these cells. leukaemia patients compared with monoallelic ATM loss or mutation.151 ATM signalling and cancer metabolism In wider large-scale studies including solid tumours, B5% of 82,152 The metabolism of tumours is almost always deregulated, cancers showed ATM aberrations (either mutation or loss). In lung cancers in particular, 8% showed ATM mutations and these consistent with the restricted access to oxygen and nutrients in 153 rapidly proliferating cells. Because ATM deficiency impairs glucose were largely mutually exclusive with TP53 mutations. In line metabolism in humans and mice,130–132 the ATM status of cancer with ATM mutations predisposing to breast cancer, ATM was downregulated in 55% of 119 breast tumours compared with cells is important in determining both the altered metabolic state 154 and the response to external metabolic stresses, which affects the adjacent tissue. One study found that ATM was particularly survival of cells within the tumour. ATM signalling activates the downregulated in solid tumours with areas of hypoxia and another that ATM loss promotes radiation resistance in gliomas, pentose phosphate pathway in response to oxidative stress, which 75,155 could support biosynthesis in cancer cells that have switched to a clues to the multiple cell stresses linked to ATM signalling. glycolytic metabolism.133,134 Conversely, reduced ATM signalling More recently, ATM alterations have been found in colon cancer. ATM mutations are found in both chromosomally unstable in solid tumours may contribute to survival by promoting 156 autophagy in the context of glucose restriction.135 Loss of ATM and microsatellite-unstable tumours. In mice, chromosomal instability from spindle checkpoint mutations cooperates with results in an increase in aberrant mitochondria in thymocytes, and 98 rescuing mitochondrial abnormalities by deletion of the ATM deficiency to accelerate tumourigenesis. It is also possible autophagy regulator Becn1 delays tumourigenesis in ATM-null that the microsatellite instability phenotype may be linked to 136 defective ATM, as recent studies proposed a role for ATM in mice. As this rescue did not affect the DNA damage response, 60,64 this study definitively shows that non-canonical ATM signalling facilitating replication-associated repair in fragile regions. ATM contributes to tumour suppression, independently of the was the gene that most frequently showed hypermethylation in 137,138 colorectal carcinomas compared with adenomas, although this documented effects of oxidative stress on DNA repair. 157 Non-canonical ATM activation using low-dose chloroquine also was not correlated with differential ATM expression. improved the metabolic profile in a mouse model of atherosclerosis, further highlighting ATM’s role in processes not Modulation of ATM signalling as therapy 131 involving exogenous DNA damage. Because activation of the DNA damage response in tumours can enable them to resist treatment with DNA-damaging agents, damage response pathways have attracted attention as targets for ATM SIGNALLING IN HUMAN CANCER AND THERAPY cancer therapy.158 The DNA damage response becomes beneficial ATM alterations in human cancer to tumour cells once they have disabled its tumour-suppressive Germline ATM mutations predispose to cancer. Different ATM function, for example by mutating a key factor, such as p53.118 The mutations have distinct, and sometimes opposing, effects on path of tumour progression and response to treatment depends different pathways, leading to a wide variation in phenotypes.139 on both ATM and p53 status.159,160 For example, ATM and ATR

& 2014 Macmillan Publishers Limited Oncogene (2014) 3351 – 3360 ATM and cancer CA Cremona and A Behrens 3356 Cooperation with other therapies. As well as radiation, ATM Table 1. Somatic ATM mutations in cancer (from COSMIC) inhibitors also sensitise cells to reoxygenation after hypoxia, Tissue No. of Percentage Selected references though it is unclear whether this relates to ATM’s role as a dimeric samples mutated redox regulator or its canonical active monomer form following oxidative damage to DNA.170 Haematopoietic 1790 11.1 Recent research has also tested the effects of ATM inhibitors in and lymphoid combination with other treatments. Fanconi anaemia-deficient tissue pancreatic cancer cells are hypersensitive to ATM inhibition,171 Lung 1040 7.2 ATM mutated/deleted thus raising the possibility of a synthetic lethal approach to in 8% of 188 lung 153 therapy. For example, ATM deficiency sensitises lymphoma cells to adenocarcinomas 172 Large intestine 782 4.6 ATM mutated in 18% of PARP inhibitors, consistent with previous work showing that ATM is required for homologous recombination repair in PARP 74 colon cancer 173 samples156 inhibitor-treated cells. ATM inhibition and p53 activation by 174 Endometrium 204 4.4 Nutlin-3 leads to apoptosis in cell lines, while ATM inhibition Prostate 331 3.9 and Akt inhibition by rapamycin leads to apoptosis in cancer cells Pancreas 387 2.6 ATM mutated/lost in with overactive Akt.124 BRCA1-deficient tumour cells may become 8% of 99 pancreatic sensitive to ATM inhibition if they inactivate 53BP1, a characteristic ductal 175 82 of resistance to PARP inhibitors. Thus, ATM inhibitors could adenocarcinomas become useful as part of a second line of defence subsequent to Upper 127 2.4 aerodigestive initial treatment, as well as in combination with other drugs. The relationship between ATM and ATR could also be exploited, tract 176 Skin 172 2.3 as ATR inhibition is synthetic lethal with ATM deficiency Kidney 847 2.1 and the ATM inhibitor KU60019 cooperates with the replication Breast 1120 1.9 stress-inducing agent temozolomide to reduce glioblastoma Central nervous 859 0.9 cell proliferation.177 The ATM inhibitor KU59403 has recently system undergone preclinical testing in mice, in combination with Ovary 713 0.7 topoisomerase poisons such as camptothecin.178 However, at Abbreviations: ATM, ataxia telangiectasia mutated; COSMIC, Catalogue Of present, there are no reports of ATM inhibitors in use in clinical Somatic Mutations In Cancer. Out of 8901 samples of all cancer types trials, though this situation is likely to change as suitable patient catalogued in the COSMIC database, 5% have ATM mutations, but this populations are identified. proportion varies according to tissue. The majority of the catalogued changes are missense mutations, unlike inherited mutations in ATM, which Therapies activating ATM? In keeping with its function as a are more frequently truncations. Also, 88% of somatic ATM mutations are tumour suppressor and ability to promote cell-cycle arrest or unique, and they are distributed throughout the protein, with a bias apoptosis, re-activation of ATM could also be useful as a cancer towards the C-terminal half around the FAT and kinase domains. The mutation data were obtained from the Sanger Institute COSMIC web site, therapy in tumours where it has been downregulated. The 199 chemotherapy drug doxorubicin activates ATM via the production release v63 http://www.sanger.ac.uk/cosmic. Note that COSMIC data 179 might underestimate the true scale of ATM aberrations in cancer, as it is of superoxide radicals and induces apoptosis via p53. In restricted to somatic mutations and does not include changes in gene addition, ATM’s ability to relax chromatin may be beneficial. expression or copy number. In addition, the database includes benign Cancer cells can become drug resistant by globally compacting neoplasms, while the samples used in the individual studies quoted were their chromatin via insulin-like growth factor 1 receptor signalling selected exclusively from patients with malignant cancer. and histone demethylation.180 Histone deacetylase inhibitors activate ATM4 and could be used as therapeutic agents to relax chromatin and hence re-sensitise cells to DNA-damaging drugs.181 ATM deficiency has been shown to sensitise cells to PARP 172 checkpoint signalling is necessary for the survival of p53-deficient inhibition. Conversely, abnormally active ATM, as seen when cells after DNA damage,161 whereas in cancers that have not lost phosphatases such as PPP2R2A are blocked, also impairs DNA repair by homologous recombination and thereby sensitises cells p53, inactivating ATM allows the survival of genomically unstable 14 cells and induces chemoresistance.159,162 to PARP inhibition. Thus, timely activation and inactivation of In tumours that are sensitive to it, ATM inhibition may have a ATM are both necessary for efficient repair, and any ATM greater effect than ATM loss: ATM inhibitors disrupt sister perturbation could inhibit the ability of cells to resist DNA chromatid exchange in cells with functional ATM, whereas in damage. However, more research is needed to determine the A-T cells sister chromatid exchange is normal.163 ATM inhibitors effects of artificial ATM activation on normal tissue. have thus been tested for anticancer activity. Interestingly, the diabetes drug metformin activates ATM, and patients who take metformin have a lower risk of developing cancer than other diabetes patients.182,183 The reasons for this are Radiosensitisation. In line with the radiosensitivity phenotype of still unclear, but it is possible that a heightened DNA damage A-T cells, the primary tests of ATM inhibitors have been in response, as well as the constitutive lowering of blood glucose combination with irradiation of cancer cells. Already several and insulin levels, contributes to tumour suppression. generations of ATM inhibitors have been shown to be effective as Alternatively, Type II diabetes is known to be a risk factor for 164 165 radiosensitisers in vitro: KU55933; CP466722; and KU60019, cancer,184 and thus metformin may indirectly lower cancer risk by with an effect 10 times more potent than KU55933 on glioma improving the patients’ metabolic profile. If this is true, metformin 166 cells. KU60019 also inhibits Akt pro-survival signalling and may not have a tumour-suppressive effect in patients who do not 166 reduces cell motility and invasion. ATM inhibitor was most have a metabolic disorder. A recent study found a differential 167 lethal when given shortly after irradiation treatment. effect of metformin on the proliferation of breast cancer cells Promisingly, ATM inhibition also showed selectivity: increasing depending on the insulin responsiveness of the patient.185 It is the killing of irradiated cells but protecting adjacent bystander also likely that germline variations in ATM, or closely related 168 cells, and preferentially sensitising cervical cancer cells over sequences, will affect the response to metformin in cancer as 169 untransformed controls. they do in diabetes.186 Nevertheless, the potential benefits of this

Oncogene (2014) 3351 – 3360 & 2014 Macmillan Publishers Limited ATM and cancer CA Cremona and A Behrens 3357 long-established drug are substantial, and clinical trials looking at 20 Mattiroli F, Vissers JH, van Dijk WJ, Ikpa P, Citterio E, Vermeulen W et al. RNF168 187 metformin as an anticancer agent are already underway. ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell 2012; In cases where ATM deficiency directly contributes to 150: 1182–1195. tumourigenesis, restoring ATM function to the tissue could 21 Savic V, Yin B, Maas NL, Bredemeyer AL, Carpenter AC, Helmink BA et al. potentially inhibit cancer development. In ATM-deficient mice, Formation of dynamic gamma-H2AX domains along broken DNA strands is transplanting ATM-competent bone marrow-derived cells delayed distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in the onset of thymic lymphoma from around 3 months to over 9 chromatin. Mol Cell 2009; 34: 298–310. months.188 If a similar effect occurs in humans, transplant therapy 22 Gudjonsson T, Altmeyer M, Savic V, Toledo L, Dinant C, Grofte M et al. TRIP12 and could be a very valuable asset in preventing cancer in A-T patients. UBR5 suppress spreading of chromatin ubiquitylation at damaged chromo- somes. Cell 2012; 150: 697–709. 23 Batchelor E, Mock CS, Bhan I, Loewer A, Lahav G. Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage. Mol Cell 2008; 30: 277–289. CONFLICT OF INTEREST 24 Derheimer FA, Kastan MB. Multiple roles of ATM in monitoring and maintaining The authors declare no conflict of interest. DNA integrity. FEBS Lett 2010; 584: 3675–3681. 25 Lee JH, Paull TT. Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene 2007; 26: 7741–7748. 26 Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to ACKNOWLEDGEMENTS genotoxic stress, and more. 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