Chromosome first aid.

Most people take the stability of chromosomes for granted. Some may imagine metaphase chromosomes lined up like a butterfly collection on a page, reassuringly in order and unchanging. However, evidence that has been accumulating for over half a century indicates that genome stability is a dynamic, not a static, process. In the 1940s natural chromosomes ends, or telomeres, were shown to be specialized structures inherently different from broken chromosome ends. McClintock demonstrated in maize that telomeres are required for the stable maintenance of linear chromosomes. Random ends generated by breakage fuse to generate dicentric chromosomes that undergo repeated cycles of breakage and fusion. Occasionally, during this cycle of breakage-fusion-bridge, chromosomes would apparently heal; their characteristic stickiness would disappear, and they would be well behaved in subsequent divisions (reviewed in Blackburn and Szostak, 1984). In addition to sporadic healing events, McClintock observed developmentally regulated, tissue-specific chromosome healing. She found that the fate of a single chromatid broken at meiosis depends on both the tissue and the time in the cell cycle at which the broken end is present. When a single broken chromatid is generated at meiosis, rounds of breakage-fusion-bridge occur in the following mitotic divisions. After fertilization, the breakage cycle continues in the endosperm tissue, while in the zygotic tissue the broken end is healed. The healed chromosome is stably propagated throughout subsequent plant development. These observations suggested that an activity that heals broken ends is present in zygotic tissue but absent in the endosperm (McClintock, 1939, 1942). In the past ten years there has been an explosive increase in our understanding of the molecular structure and function of telomeres. However, only very recently has the process of chromosome healing, initially documented over 50 years ago, been understood at the molecular level. Telomere Structure and Synthesis Telomeric sequences, first characterized in ciliates, are remarkably conserved throughout evolution. Functional telomeres consist of many tandem repeats of simple G-rich sequences. In Tetrahymena there are approximately 70 (TTGGGG) repeats, while in humans there are more than 600 (TTAGGG) repeats found at all chromosome ends. The number of repeats on any given chromosome varies, giving telomeric restriction fragments a characteristic fuzzy appearance on Southern blots. Because most DNA polymerases are not able to replicate completely the molecular end of a DNA molecule, the mechanism of telomere replication was the topic of speculation for many years (reviewed in Blackburn and Szostak, 1984). However, the discovery of the enzyme telomerase in Tetrahymena presented a simple explanation for both the structure and Minireview