8-ATM' - REVIEWS ATM AND RELATED PROTEIN KINASES...

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REVIEWS ‘Cancer is a genetic disease of the somatic cell’. This cliché makes increasing sense with the discovery of every new oncogene and tumour-suppressor gene. The road to cancer is paved with alterations in the sequence and organization of the cellular genome that range from single-nucleotide substitutions to gross chromosomal aberrations. These represent deviations from a prime requisite for cellular homeostasis: maintenance of genome stability. As the neoplastic cellular phenotype progresses, genomic stability continues to deteriorate, leading to a vicious cycle of genomic aberrations and advancing malignancy 1 . Although sequence variation of germline DNA is essential for maintaining genetic variability, changes in DNA sequence in somatic cells are usually unwanted, and cells possess strict safeguards against such changes 2 . The crucial event that signifies the onset of malignancy is thought to be a single genomic alteration, the out- come of which might be as subtle as a slight change in the amount of a protein, or the substitution of a single amino acid. The occurrence and fixation of such an alteration signifies the failure of a mechanism that should have detected the DNA lesion or mismatch that caused the mutation and evoked the response that is required to restore the original sequence and leave the cellular life cycle unperturbed. Sequence alterations in DNA arise from sponta- neous chemical changes in DNA constituents, replica- tion errors and damage inflicted on the DNA 3 . The greatest challenge to genome stability comes from DNA-damaging agents that can be either endogenous (they form during normal cell metabolism) or exoge- nous (they come from the environment). Damaging agents such as radiation and reactive chemicals are capa- ble of inducing a plethora of DNA lesions. Some are extremely cytotoxic if not repaired, whereas others are mutagenic and can affect the production, structure and function of cellular proteins, with consequences ranging from malfunction of the cell to malignant transforma- tion (FIG. 1) . It is not surprising, therefore, that many mutagens are also carcinogens, and that there is a high correlation between their carcinogenic and mutagenic potencies 4 . How does the cell defend itself against this serious existential threat? The basic cellular response is to repair the damage, but the type and amount of damage might overwhelm the survival response machinery to the extent that programmed cell death (apoptosis) is initiated 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 will focus on the road taken by the cell when chances for ATM AND RELATED PROTEIN KINASES: SAFEGUARDING GENOME INTEGRITY Yosef Shiloh Maintenance 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 the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA
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