N ew Functions for Telom erase

467 Eukaryotic chromosomes terminate in specialized chromatin formed by repeated arrays of guanine-rich DNA bound by telomere-specific binding proteins. These structures, called telomeres, maintain chromosomal integrity since loss of telomeric sequences or mutations of telomere binding proteins leads to genomic instability that eventually compromises cell viability (1,2). Telomeres are synthesized in most cells by the reverse transcriptase telomerase, a ribonucleoprotein comprised of two core components: an RNA subunit (TERC) and a rate-limiting protein subunit (TERT) (1). The RNA component provides the template for telomere synthesis while TERT is the catalytic subunit. In addition, several telomere-specific binding proteins have been described to play critical roles in regulating telomere length, integrity and function (3). Together, these factors, telomeres, telomerase, and telomere binding proteins, control chromosomal stability and cell replicative lifespan (4). Alterations in both karyotypic stability and proliferative potential are hallmarks of cancer, and disruption of the mechanisms that regulate telomere homeostasis occurs in the majority of human cancers (2). Several lines of experimentation indicate that the telomere attrition associated with progressive cell division suppresses tumor formation by providing a barrier to proliferation (5). However, when telomeres reach lengths that no longer protect chromosome ends, the majority of cells harboring such dysfunctional telomeres die by apoptosis induced by widespread chromosomal instability (crisis) (6∼8). However, rare cells survive crisis and maintain stable telomere lengths (6,9). The majority of such cells accomplish this telomere stabilization through the constitutive activation of telomerase (10) although some cells activate an alternative mechanism of telomere lengthening (ALT) (11). In yeast, ALT accomplishes telomere elongation through recombination, which may also occur in mammalian cells (12,13). Thus although telomere erosion limits cell lifespan, excessive telomere loss can also drive genomic instability (2). Thus, telomere biology is linked to malignant transformation in several ways. First, telomeres, both telomere length and the actions of telomere binding proteins, control karyotypic stability and suppress limit replicative lifespan (14∼16). However in the setting of p53 loss, compromised chromosome end protection resulting from telomere dysfunction may drive the formation of cancers through the development of non-reciprocal translocations and chromosomal fusions (7). In addition, constitutive activation of telomerase, which stabilizes telomeres, facilitates immortalization (17,18), a critical event during cell transformation, and inhibition of telomerase function in human cancer cell limits replicative potential (19∼22). Moreover, since most human cancer cell lines and tumors express telomerase activity (23), abundant evidence exists to support the notion that constitutive telomerase expression plays a critical role in cancer development. In addition, ectopic introduction of hTERT cooperates with oncogene expression to convert primary human cells into cells capable of growing in an anchorage-independent manner and as tumors in animals (24∼ 27), suggesting that the immortalization facilitated by telomerase contributes directly to transformation. However, recent developments suggest that telomerase may play a more complex role in cancer development. N ew Functions for Telom erase