to accumulate mutations more readily. Similarly, a rare genetic disease known as ataxia telangiectasia is caused by a defect in ATM, one of the protein kinases that are activated in response to x-ray-induced DNA damage; patients with this disease are very sensitive to x-rays and suffer from increased rates of cancer.
What happens if DNA damage is so severe that repair is not possible? The answer differs in different organisms. Unicellular organisms such as budding yeast arrest their cell cycle to try to repair the damage, but the cycle resumes even if the repair cannot be completed. For a single-celled organism, life with mutations is apparently better than no life at all. In multicellular organisms, however, the health of the organism takes precedence over the life of an individual cell. Cells that divide with severe DNA damage threaten the life of the organism, since genetic damage can often lead to cancer and other diseases. Thus, animal cells with severe DNA damage do not attempt to continue division, but instead commit suicide by undergoing apoptosis. Thus, unless the DNA damage is repaired, the DNA damage response can lead to either cell-cycle arrest or cell death. DNA damage-induced apoptosis often depends on the activation of p53. Indeed, it is this apoptosis-promoting function of p53 that is apparently most important in protecting us against cancer.
many Human Cells Have a Built-In Limitation on the number of Times They Can divide
Many human cells divide a limited number of times before they stop and undergo a permanent cell-cycle arrest. Fibroblasts taken from normal human tissue, for example, go through only about 25–50 population doublings when cultured in a standard mitogenic medium. Toward the end of this time, proliferation slows down and finally halts, and the cells enter a nondividing state from which they never recover. This phenomenon is called replicative cell senescence.
Replicative cell senescence in human fibroblasts seems to be caused by changes in the structure of the telomeres, the repetitive DNA sequences and associated proteins at the ends of chromosomes. As discussed in Chapter 5, when a cell divides, telomeric DNA sequences are not replicated in the same manner as the rest of the genome but instead are synthesized by the enzyme telomerase. Telomerase also promotes the formation of protein cap structures that protect the chromosome ends. Because human fibroblasts, and many other human somatic cells, do not produce telomerase, their telomeres become shorter with every cell division, and their protective protein caps progressively deteriorate. Eventually, the exposed chromosome ends are sensed as DNA damage, which activates a p53-dependent cell-cycle arrest (see Figure 17–62). Rodent cells, by contrast, maintain telomerase activity when they proliferate in culture and therefore do not have such a telomere-dependent mechanism for limiting proliferation. The forced expression of telomerase in normal human fibroblasts, using genetic engineering techniques, blocks this form of senescence. Unfortunately, most cancer cells have regained the ability to produce telomerase and therefore maintain telomere function as they proliferate; as a result, they do not undergo replicative cell senescence.
abnormal proliferation signals Cause Cell-Cycle arrest or apoptosis, Except in Cancer Cells
Many of the components of mitogenic signaling pathways are encoded by genes that were originally identified as cancer-promoting genes, because mutations in them contribute to the development of cancer. The mutation of a single amino acid in the small GTPase Ras, for example, causes the protein to become permanently overactive, leading to constant stimulation of Ras-dependent signaling pathways, even in the absence of mitogenic stimulation. Similarly, mutations that cause an overexpression of Myc stimulate excessive cell growth and proliferation and thereby promote the development of cancer (discussed in Chapter 20).