Telomeres and their possible role in chromosome stabilization.
The evidence to date generally supports the hypothesis that telomere capping makes chromosome fragments refractory to subsequent rejoining events, but this control may be somewhat relaxed after chromosome breakage. Cell survival requires that the fragments rejoin before metaphase. Unprotected ends such as those produced by DNA damage are subject to degradation, presumably by endogenous cellular exo- and endonucleases. Telomere repeat sequences may be added to broken chromosome ends to protect the ends from further degradation. That telomeric DNA does not always prevent rejoining raises interesting questions as to what constitutes capping, and how rapidly it occurs after DNA damage in relation to chromosome break rejoining. The prevention of degradation and control of rejoining may be mediated by telomere-specific binding proteins, especially the telomere terminal binding protein [Gualberto et al., 1992; Longtine et al., 1989; Price, 1990; Price and Cech, 1989]. Some of these proteins may be involved in scavenging telomeric DNA when the cell senses that chromosomal breaks have occurred. This mechanism is consistent with the observations of Murnane and Yu [1993], who found that a plasmid with telomere sequences was stably integrated in vivo into a chromosome terminal breakpoint lacking telomere repeats. It is also consistent with the high frequency of interstitial telomere sequences observed in normal cells; a history of DNA damage and repair may be recorded by these sequences (Ijdo et al., 1991]. Although chromosome break rejoining is an efficient process in eukaryotic cells, some breaks are never rejoined and can result in terminal deletions and chromatid and isochromatid deletions at metaphase. It is unclear why these breaks are not rejoined, but it may be due to one or more of the following: 1) chance: broken chromosomes are separated, do not approach sufficiently close to one another, and are consequently physically unable to rejoin; 2) a large number of added telomere repeat sequences indicating to the cell that the chromosome has an authentic telomere; 3) some other DNA modification event that protects DNA ends from degradation, e.g., folding back of DNA ends to form a hairpin, as has been implicated in VDJ recombination [Lieber, 1993].
Day
J P
JP
Laboratory of Radiobiology and Environmental Health, University of California, San Francisco 94143-0750.
Marder
B A
BA
Morgan
W F
WF
D000818:Animals; D002869:Chromosome Aberrations / Q000502:physiology*; D006801:Humans; D016615:Telomere / Q000502:physiology*