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The ATM Protein Kinase: Regulating the Cellular Response to Genotoxic Stress, and More

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The ATM Protein Kinase: Regulating the Cellular Response to Genotoxic Stress, and More REVIEWS DNA DAMAGE The ATM protein kinase: regulating the cellular response to genotoxic stress, and more Yosef Shiloh and Yael Ziv Abstract | The protein kinase ataxia-telangiectasia mutated (ATM) is best known for its role as an apical activator of the DNA damage response in the face of DNA double-strand breaks (DSBs). Following induction of DSBs, ATM mobilizes one of the most extensive signalling networks that responds to specific stimuli and modifies directly or indirectly a broad range of targets. Although most ATM research has focused on this function, evidence suggests that ATM-mediated phosphorylation has a role in the response to other types of genotoxic stress. Moreover, it has become apparent that ATM is active in other cell signalling pathways involved in maintaining cellular homeostasis. This Review is dedicated with deep indebtedness and Unrepaired DSBs can severely disrupt DNA replica- appreciation to the memory of Maimon M. Cohen tion in proliferating cells, usually leading to cell death, (1935–2007), a pioneer in human genetics and the or leave chromosomal aberrations that may initiate a research of ataxia-telangiectasia. vicious cycle of further genomic alterations, setting the stage for cancer formation. Protein phosphorylation is a central post-translationa­l The vigorous cellular response to DSBs is a highly modification (PTM) in cellular signalling. Phosphoryl­ ordered cascade of events divided into several major ation can modulate substrate activity, stability, inter­action stages, which partly overlap in time (BOX 2; FIG. 1a). Its early with other proteins and subcellular localization and phase is characterized by the recruitment to DSB sites often primes it for additional PTMs. Phosphorylation– of a large, heterogeneous group of proteins collectively dephosphorylation cycles can dynamically fine-tune the dubbed ‘sensors’ or ‘mediators’, which form large pro- function and turnover of a protein. Cascades of protein tein complexes that appear as nuclear foci when imaged phosphorylation are often the backbones of signalling under a fluorescence microscope. This is accompanied by pathways. Such cascades can be initiated by the activa- the activation of ‘transducers’, which are protein kinases tion of an apical protein kinase that alone is sufficient to such as ATM that relay a strong, wide-spread signal to mobilize an extensive signalling network. numerous downstream effectors. Some of these effectors The Ser/Thr protein kinase ataxia-telangiectasia are sensors, hence a feedback loop is created to maintain mutated (ATM) is a prime example of this principle. The the construction and shape of the DSB-associated focus gene encoding ATM is mutated in the human genomic as well as the processes within this structure. This leads (BOX 1) The David and Inez Myers instability syndrome ataxia-telangiectasia . This to the modulation of pathways and processes through- Laboratory for Cancer disorder involves a marked defect in responding to a out the cell in which the various effectors are key players. Genetics, Department of severe DNA lesion, the double-strand break (DSB)1,2. An important determinant of the broad span of the DSB Human Molecular Genetics Not surprisingly, ATM is best known for its role as a response is the extensive range of substrates of the main and Biochemistry, 5–7 Sackler School of Medicine, chief mobilizer of the cellular response to this DNA transducer of this response, ATM . Tel Aviv University, lesion. DNA DSBs can be generated by DNA damagin­g Recent work suggests that ATM might also be Tel Aviv 69978, Israel. agents, following the collapse of stalled replication forks3 involved in the responses to other types of genotoxi­c Correspondence to Y.S. or in response to uncapped telomeres4. DSBs are also stresses, perhaps in a less predominant position com- e‑mail: obligate intermediates in meiotic recombination and in pared with its leading role in the DSB response. [email protected] doi:10.1038/nrm3546 the assembly of the genes encoding antigen receptors Furthermore, evidence is steadily accumulating that the Published online during lymphocyte maturation through V(D)J and class broad capacity of ATM as a protein kinase is exploited 13 March 2013 switch recombination (not discussed in this Review). in undamaged cells in other signalling pathways that NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 14 | APRIL 2013 | 197 © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Box 1 | Ataxia-telangiectasia of a HEAT domain (common to huntingtin, elongation facto­r 3, protein phosphatase 2A (PP2A) and yeast target­ Ataxia-telangiectasia (Online Mendelian Inheritance in Man (OMIM) database ID: of rapamycin 1 (TOR1)) and a few interaction sites with 208900) is a human genomic instability disorder inherited in an autosomal recessive other proteins (reviewed in REF. 10). Other notable sites manner1,129. It is caused by mutations in ATM (ataxia-telangiectasia mutated), are those that become decorated with PTMs during which encodes the ATM protein187,188. The disease is characterized by progressive (FIG. 1b) neurodegeneration that affects mainly the cerebellum and develops into severe ATM activation (see below). Clearly, the lack neuromotor dysfunction, telangiectasia (that is, the dilation of blood vessels observed of structural data, which probably stems from technical primarily in the eyes), immunodeficiency that spans the B cell and T cell systems, challenges in ATM crystallization, is currently hinder- thymic and gonadal atrophy, marked predisposition to malignancies (primarily ing progress in further understanding the functional lymphoreticular), increased serum levels of α-fetoprotein and carcinoembryonic significanc­e of ATM domains. antigen, acute sensitivity to ionizing radiation, and, occasionally, growth retardation, premature ageing and insulin resistance. The hallmarks of the cellular phenotype of A PIKK trinity? The PI3K domain is a signature of ataxia-telangiectasia are increased chromosomal breakage, premature senescence of PIKKs, most of which are active in various stress cultured primary fibroblasts and sensitivity to DNA-damaging agents, which is most responses8,9. Other members of this group are ATR evident when cells from patients with ataxia-telangiectasia are treated with physical (ATM and RAD3‑related), DNA-PKcs (DNA-dependent or chemical double-strand break (DSB)-inducing agents. This sensitivity represents a marked defect in the activation of the cellular response to DSBs, the chief mobilizer of protein kinase catalytic subunit), SMG1 (suppressor of which is ATM. Notably, however, typical readouts of the DSB response are attenuated mutagenesis in genitalia 1), mTOR (mammalian TOR) in these cells rather than completely abolished, attesting to the activity of redundant and TRRAP (transformation/transcription domain- protein kinases. associate­d protein; the only member of this group that The classic ataxia-telangiectasia phenotype is caused by homozygosity or compound lacks catalytic activity). The PI3K‑like domain and two heterozygosity for ATM‑null alleles, which typically truncate ATM or inactivate it via other C-terminal domains, FAT (conserved in FRAP, missense mutations (see Leiden Open Variation Database). Milder forms of the disease, ATM and TRRAP) and FATC (FAT C‑terminal) (FIG. 1b), which are characterized by later onset or slower progression of symptoms, are are shared among PIKKs. associated with mutations that leave residual amounts of functional ATM protein. Three of the PIKKs are major players in responses to Another disorder, ataxia-telangiectasia‑like disorder (ATLD), is similar to mild ataxia- genotoxic stresses: ATM, DNA-PKcs and ATR. Notably, telangiectasia, with a later age of onset and slower progression than the classic condition189. ATLD is caused by hypomorphic mutations in MRE11A, which encodes a they preferentially phosphorylate their respective targets component of the MRN (MRE11–RAD50–NBS1) complex190 (see main text). on Ser or Thr residues followed by Glu (S/T‑Q motif). The Many of the major symptoms of ataxia-telangiectasia are readily explained by the diversity of their functions has recently come to light in a defective response to physiological DSBs and DSBs induced by DNA-damaging agents. similar way: traditionally, each was associated with a spe- However, the debate continues over the cause of the most devastating symptom of the cific canonical pathway, but awareness is growing of other disease — the relentless cerebellar degeneration. This discussion is continuously signalling pathways that they regulate. DNA-PKcs is the fertilized by the discoveries of new roles for ATM in maintaining cellular homeostasis. catalytic subunit of the DNA‑PK holoenzyme, which also contains the KU70–KU80 heterodimer. It is best known for its central role in the non-homologous end-joining respond to various stimuli or physiological situations. (NHEJ) DSB repair pathway11,12 (BOX 2), but its involve- The role of ATM under these conditions is probably less ment in other processes, such as cell proliferation and pronounced than in acute DNA damage and hence regulation of oxidative stress, is being noted13,14. ATR has less visible than in the ATM-mediated DNA damage a major role in coordinating DNA replication origin firing response (DDR) — ATM’s main claim to fame. Some and guarding replication fork stability, and its canonical of these pathways are not nuclear and are involved in pathway activates a DDR network following replication various metabolic
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