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Unformatted text preview: BIOLOGY OF NEOPLASIA Role of Telomeres and Telomerase in the Pathogenesis of Human Cancer By William C. Hahn Abstract: Specialized nucleoprotein structures, termed telomeres, cap the ends of human chromosomes. These terminal structures, composed of repetitive arrays of gua- nine-rich hexameric DNA together with specific telomere- binding proteins, play essential roles in protecting the chro- mosome from damage and degradation. In addition, several lines of evidence implicate telomere maintenance as an important regulator of cell life span. Activation of telom- erase, a dedicated reverse transcriptase that synthesizes telomeric sequences, is strongly associated with cancer, and recent observations confirm that telomeres and telomerase perform important roles in both suppressing and facilitating malignant transformation. These dual functions of telomere biology are evident in the clinical manifestations of the multisystem syndrome, dyskeratosis congenita, forms of which display defects in telomerase function. Recent ad- vances in our understanding of telomere biology indicate that the manipulation of telomeres and telomerase will lead to clinically significant applications in the diagnosis, preven- tion, and treatment of neoplastic disease. J Clin Oncol 21:2034-2043. 2003 by American Society of Clinical Oncology. C ANCER ENCOMPASSES a diverse set of diseases that not only originate from almost every tissue but also display remarkable heterogeneity in presentation and prognosis. Despite this immense range of clinical characteristics, all human tumors share a limited set of behaviors that define the malignant state. 1 Among these hallmarks, unlimited replicative potential and widespread genomic disarray are among the most common characteristics exhibited by human cancer cells. Although sev- eral distinct molecular pathways regulate specific aspects of each of these phenotypes, emerging evidence now implicates the maintenance and function of the specialized chromosomal ter- minal structures, termed telomeres, as essential regulators of both cell life span and chromosomal integrity. This review highlights recent advances in our understanding of mammalian telomere biology as it relates to cancer and discusses current approaches to exploit this knowledge to develop novel antineo- plastic therapeutic approaches. TELOMERE STRUCTURE AND MAINTENANCE Telomeres are composed of both repeated DNA elements and specific DNA-binding proteins, which together form the ends of eukaryotic chromosomes (Fig 1). 2 Although the sequence of these terminal structures varies among different organisms, all telomeres are composed of large arrays of short guanine-rich sequences, such as those found in mammalian cells, 5 9- TTAGGG-3 9 ....
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