Telomere-Dependent Chromosomal Instability

Abstract

Telomeres are specialized DNA-protein structures at the ends of the linear chromosomes. In mammalian cells, they are composed of multifold hexameric TTAGGG repeats and a number of associated proteins. The double-stranded telomeric DNA ends in a 3' single stranded overhang of 150 to 300 base pair (bp) which is believed to be required for a higher order structure (reviewed in (Blackburn, 2001)). One important model is that the telomeres form loop structures, the T-loops, and by invasion of the 3' overhang into the duplex region of the double stranded part protect the DNA against degradation and hinder the cellular machinery to recognize the ends as broken DNA, thus providing chromosomal integrity (Griffith et al, 1999). If telomeres become critically short they loose their capping function, become sticky, and are prone to illegitimate chromosome end-to-end fusions. The resulting dicentric chromosomes are highly unusable and because of bridge-fusion-breakage cycles they give rise to chromosomal translocations, deletions, and amplifications. Thus, critically short telomeres are thought to be responsible for the onset of genomic instability. In addition, we provide evidence that in a length-independent manner telomeres can confer to genomic instability by forming telomericaggregates which through chromosomal dys-locations contribute to chromosomal aberrations.