REVIEWS‘Cancer is a genetic disease of the somatic cell’.Thiscliché makes increasing sense with the discovery ofevery new oncogene and tumour-suppressor gene.Theroad to cancer is paved with alterations in the sequenceand organization of the cellular genome that range fromsingle-nucleotide substitutions to gross chromosomalaberrations. These represent deviations from a primerequisite for cellular homeostasis: maintenance ofgenome stability.As the neoplastic cellular phenotypeprogresses,genomic stability continues to deteriorate,leading to a vicious cycle of genomic aberrations andadvancing malignancy1.Although sequence variation of germline DNA isessential for maintaining genetic variability,changes inDNA sequence in somatic cells are usually unwanted,and cells possess strict safeguards against such changes2.The crucial event that signifies the onset of malignancyis thought to be a single genomic alteration, the out-come of which might be as subtle as a slight change inthe amount of a protein,or the substitution of a singleamino acid.The occurrence and fixation of such analteration signifies the failure of a mechanism thatshould have detected the DNA lesion or mismatch thatcaused the mutation and evoked the response that isrequired to restore the original sequence and leave thecellular life cycle unperturbed.Sequence alterations in DNA arise from sponta-neous chemical changes in DNA constituents,replica-tion errors and damage inflicted on the DNA3.Thegreatest challenge to genome stability comes fromDNA-damaging agents that can be either endogenous(they form during normal cell metabolism) or exoge-nous (they come from the environment).Damagingagents such as radiation and reactive chemicals are capa-ble of inducing a plethora of DNA lesions.Some areextremely cytotoxic if not repaired,whereas others aremutagenic and can affect the production,structure andfunction of cellular proteins,with consequences rangingfrom malfunction of the cell to malignant transforma-tion (FIG.1). It is not surprising, therefore,that manymutagens are also carcinogens,and that there is a highcorrelation between their carcinogenic and mutagenicpotencies4.How does the cell defend itself against this seriousexistential threat? The basic cellular response is torepair the damage,but the type and amount of damagemight overwhelm the survival response machinery tothe extent that programmed cell death (apoptosis) isinitiated instead (FIG.1). The mechanism of this impor-tant choice between attempts at survival and pro-grammed death is not entirely clear,but here we willfocus on the road taken by the cell when chances forATM AND RELATED PROTEINKINASES:SAFEGUARDING GENOMEINTEGRITYYosef ShilohMaintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response — a cornerstone of genome stability — occurs by a swift transduction of theDNA-damage signal to many cellular pathways. A prime example is the cellular response to DNAdouble-strand breaks, which activate the ATM protein kinase that, in turn, modulates numeroussignalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). Understanding ATM’s mode of action provides new insights into theassociation between defective responses to DNA damage and cancer, and brings us closer toresolving the issue of cancer predisposition in some A-T carriers.NATURE REVIEWS | CANCER VOLUME 3 | MARCH 2003 | 155The David and Inez MyersLaboratory for GeneticResearch,Department ofHuman Genetics andMolecular Medicine,Sackler School of Medicine,Tel Aviv University,Tel Aviv 69978, Israel.e-mail: [email protected]:10.1038/nrc1011CELL-CYCLE CHECKPOINTSRegulatory mechanisms that donot allow the initiation of a newphase of the cell cycle before theprevious one is completed,ortemporarily arrest cell-cycleprogression in response to stress.DNA damage activates specificcheckpoints at the G1–S andG2–M boundaries and in the S phase, with each one based ona different mechanism.156 | MARCH 2003 | VOLUME 3 www.nature.com/reviews/cancerREVIEWSThe DSB model of the DNA-damage responseDSBs are naturally formed and sealed during processessuch as meiotic recombination and the assembly of theT-cell receptor and immunoglobulin genes via V(D)Jrecombination, in T cells and B cells, respectively. It issafe to assume that cellular DSB repair mechanisms(BOX 2)maintain continuous,low-level activity, ensuringthat the occurrence and resealing of these breaks leavethe cell unharmed.But when DSBs are inflicted on thegenome by damaging agents,such as free radicals orionizing radiation, their threat to cell life is sufficientlyserious to set in motion, within minutes, a rapidlymounting, decisive DNA-damage response10–12.Recent models64depict the DSB response as develop-ing through a series of steps (FIG.2).According to thesemodels,DSBs might first be detected by sensor proteinsthat recognize the DNA lesion itself or possibly chro-matin alterations that follow DNA breakage. The brokenends are then processed — their chemical nature is ran-dom,so they cannot serve directly as substrates for repairmechanisms.Then,the transducers are brought intoaction; these convey the damage signal to downstreameffectors.It is this relay system from transducers to effec-tors that enables a single transducer to quickly affect theoperation of many pathways.The transducers might alsobe involved in the assembly of DNA-repair complexes atthe site of the damage (BOX 2), so DSB repair and sig-nalling are probably concomitant and functionally linked(FIG.2).In the case of DSBs, the initial and primary trans-ducer is ATM — although related protein kinases are alsoinvolved — which transmits the message via a standardsignalling mode: protein phosphorylation.The PI3K-related protein kinase familyATM belongs to a conserved family of proteins,most ofwhich possess a serine/threonine kinase activity18–22.Interestingly, all of these proteins contain a domain withmotifs that are typical of the lipid kinase phosphatidyli-nositol 3-kinase (PI3K) (FIG. 3), so they are dubbed‘PI3K-like protein kinases’(PIKKs).The PI3K domainharbours the catalytic site of the active protein kinases ofthe PIKK family. The mammalian members of this fam-ily,at present, include five protein kinases — ATM,AT R,ATX/SMG-1,mTOR/FRAP and DNA-PKcs (FIG.3) —and TRRAP,which is a component of histone acetyl-transferase complexes23,24.The active protein kinases inthe