Most prokaryotes have a circular chromosome, with no ends, so the shortening of DNA does not occur. But what pro- tects the genes of linear eukaryotic chromosomes from being eroded away during successive rounds of DNA replication? Eukaryotic chromosomal DNA molecules have special nucleotide sequences called telomeres at their ends. Telomeres do not contain genes; instead, the DNA typically con- sists of multiple repetitions of one short nucleotide sequence. In each human telomere, for example, the six-nucleotide sequence TTAGGG is repeated between 100 and 1,000 times.Telomeres have two protective functions. First, specific proteins associated with telomeric DNA prevent the stag- gered ends of the daughter molecule from activating the cell’s systems for monitoring DNA damage. (Staggered ends of a DNA molecule, which often result from double-strand breaks, can trigger signal transduction pathways leading to cell cycle arrest or cell death.) Second, telomeric DNA acts as a kind of buffer zone that provides some protection against the organism’s genes shortening, somewhat like how the plastic-wrapped ends of a shoelace slow down its unraveling. Telomeres do not prevent the erosion of genes near the ends of chromosomes; they merely postpone it.
As shown in Figure 16.20, telomeres become shorter dur- ing every round of replication. Thus, as expected, telomeric DNA tends to be shorter in dividing somatic cells of older individuals and in cultured cells that have divided But what about cells whose genome must persist virtually unchanged from an organism to its offspring over many gen- erations? If the chromosomes of germ cells became shorter in every cell cycle, essential genes would eventually be miss- ing from the gametes they produce. However, this does not occur: An enzyme called telomerase catalyzes the lengthening of telomeres in eukaryotic germ cells, thus restoring their original length and compensating for the shortening that occurs during DNA replication. This enzyme contains its own RNA molecule that it uses as a template to artificiallyNormal shortening of telomeres may protect organisms from cancer by limiting the number of divisions that somatic cells can undergo. Cells from large tumors often have unusu- ally short telomeres, as we would expect for cells that have undergone many cell divisions. Further shortening would presumably lead to self-destruction of the tumor cells. Telomerase activity is abnormally high in cancerous somatic cells, suggesting that its ability to stabilize telomere length may allow these cancer cells to persist. Many cancer cells
do seem capable of unlimited cell division, as do immortal strains of cultured cells. For several years, researchers have studied inhibition of telomerase as a possible cancer therapy. While studies that inhibited telomerase in mice with tumors have led to the death of cancer cells, even- tually the cells have restored the length of their telomeres by an alternative pathway. This is an area of ongoing research that may eventually yield useful cancer treatments.
