9. Telomeres are simple repeats that seal the ends of chromosomes

18.9 Telomeres are simple repeats that seal the ends of chromosomes

Key terms defined in this section
Telomere is the natural end of a chromosome; the DNA sequence consists of a simple repeating unit with a protruding single-stranded end that may fold into a hairpin.

Another essential feature in all chromosomes is the telomere, which "seals" the end. We know that the telomere must be a special structure, because chromosome ends generated by breakage are "sticky" and tend to react with other chromosomes, whereas natural ends are stable.


We can apply two criteria in identifying a telomeric sequence:



  • It must lie at the end of a chromosome (or, at least, at the end of an authentic linear DNA molecule).
  • It must confer stability on a linear molecule.

Several telomeric sequences have been obtained from linear DNA molecules present in the genomes of lower eukaryotes. The same type of sequence is found in plants and man, so the construction of the telomere seems to follow a universal principle. Each telomere consists of a long series of short, tandemly repeated sequences. All such telomeric sequences can be written in the general form Cn(A/T)m, where n>1 and m is 1 V4.


The problem of finding a system that offers an assay for function again has been brought to the molecular level by using yeast. All the plasmids that survive in yeast (by virtue of possessing ARS and CEN elements) are circular DNA molecules. Linear plasmids are unstable (because they are degraded). Could an authentic telomeric DNA sequence confer stability on a linear plasmid?


Fragments from yeast DNA that prove to be located at chromosome ends can be identified by such an assay. And a region from the end of a known natural linear DNA molecule Xthe extrachromosomal rDNA of Tetrahymena Xis able to render a yeast plasmid stable in linear form.


Some indications about how a telomere functions are given by some unusual properties of the ends of linear DNA molecules. In a trypanosome population, the ends are variable in length. When an individual cell clone is followed, the telomere grows longer by 7 V10 bp (1 V2 repeats) per generation. Even more revealing is the fate of ciliate telomeres introduced into yeast. After replication in yeast, yeast telomeric repeats are added onto the ends of the Tetrahymena repeats.


Addition of telomeric repeats to the end of the chromosome in every replication cycle could solve the problem of replicating linear DNA molecules discussed in 12 The replicon. The addition of repeats by de novo synthesis would counteract the loss of repeats resulting from failure to replicate up to the end of the chromosome. Extension and shortening would be in dynamic equilibrium (for review see Blackburn and Szostak, 1984; Zakian, 1989).


If telomeres are continually being lengthened (and shortened), their exact sequence may be irrelevant. All that is required is for the end to be recognized as a suitable substrate for addition. This explains how the ciliate telomere functions in yeast.


We do not know how the complementary (C-A-rich) strand of the telomere is assembled, but we may speculate that it could be synthesized by using the 3′ VOH of a terminal G-T hairpin as a primer for DNA synthesis.


The telomere end has several unusual properties. It has a single-stranded extension of the G-T-rich strand, usually for 14 V16 bases. But isolated telomeric fragments do not behave as though they contain single-stranded DNA; instead they show aberrant electrophoretic mobility and other properties.




Figure 18.23 The unusual behavior of telomeric fractions may be explained by G-G interactions. In the upper model a duplex hairpin is formed by G-G pairing. In the lower model, a G quartet is formed when 1 G is contributed by each of 4 repeating units.

A model for the structure of the end is depicted in Figure 18.23. It proposes the existence of a "quartet" of G residues, formed by an association of one G from each repeating unit. In the example in the figure, the second G of each of four successive T2G4 units forms a member of the quartet. The rest of the repeating unit is looped out. The association between the G residues requires that two of them change the orientation of the base with regard to the sugar (from the usual anti to the unusual syn configuration). Since each repeating unit has more than one G, more than one quartet could be formed if other G residues associate, in which case quartets might be stacked upon one another in a helical manner. While the formation of this structure attests to the unusual properties of the G-rich sequence in vitro, it does not of course demonstrate whether the quartet forms in vivo (Henderson et al., 1987; Williamson et al., 1989).




Reviews
Blackburn, E. H. and Szostak, J. W. (1984). The molecular structure of centromeres and telomeres. Ann. Rev. Biochem 53, 163-194.
Zakian, V. A. (1989). Structure and function of telomeres. Ann. Rev. Genet. 23, 579-604.

Research
Henderson, E., Hardin, C. H., Walk, S. K., Tinoco, I., and Blackburn, E. H. (1987). Telomeric oligonucleotides form novel intramolecular structures containing guanine-guanine base pairs. Cell 51, 899-908.
Williamson, J. R., Raghuraman, K. R., and Cech, T. R. (1989). Monovalent cation-induced structure of telomeric DNA: the G-quartet model. Cell 59, 871-880.



Genes VII
Genes VII
ISBN: B000R0CSVM
EAN: N/A
Year: 2005
Pages: 382

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