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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 4)

Telomerase DNA polymerase is unable to replicate the tips of chromosomes, resulting in the loss of DNA at the specialized ends of chromosomes (called telomeres) with each replication cycle. At birth, human telomeres are 15- to 20-kb pairs long and are composed of tandem repeats of a six-nucleotide sequence (TTAGGG) that associate with specialized telomere-binding proteins to form a T-loop structure that protects the ends of chromosomes from being mistakenly recognized as damaged. The loss of telomeric repeats with each cell division cycle causes gradual telomere shortening, leading to growth arrest (called replicative senescence) when one or more critically. | Chapter 080. Cancer Cell Biology and Angiogenesis Part 4 Telomerase DNA polymerase is unable to replicate the tips of chromosomes resulting in the loss of DNA at the specialized ends of chromosomes called telomeres with each replication cycle. At birth human telomeres are 15- to 20-kb pairs long and are composed of tandem repeats of a six-nucleotide sequence TTAGGG that associate with specialized telomere-binding proteins to form a T-loop structure that protects the ends of chromosomes from being mistakenly recognized as damaged. The loss of telomeric repeats with each cell division cycle causes gradual telomere shortening leading to growth arrest called replicative senescence when one or more critically short telomeres triggers a p53-regulated DNA-damage checkpoint response. Cells can bypass this growth arrest if pRB and p53 are nonfunctional but cell death ensues when the unprotected ends of chromosomes precipitate chromosome fusions or other catastrophic DNA rearrangements termed crisis . The ability to bypass telomere-based growth limitations is thought to be a critical step in the evolution of most malignancies. This occurs by the reactivation of telomerase expression in cancer cells. Telomerase is an enzyme that adds TTAGGG repeats onto the 3 ends of chromosomes. It contains a catalytic subunit with reverse transcriptase activity hTERT and an RNA component that provides the template for telomere extension. Most normal somatic cells do not express sufficient telomerase to prevent telomere attrition with each cell division. Exceptions include stem cells such as those found in hematopoietic tissues gut and skin epithelium and germ cells that require extensive cell division to maintain tissue homeostasis. More than 90 of human cancers express high levels of telomerase that prevent telomere exhaustion and allow indefinite cell proliferation. In vitro experiments indicate that inhibition of telomerase activity leads to tumor cell apoptosis. Major efforts are .