Telomeres, chromosome instability and cancer

Abstract

Telomeres are composed of repetitive G-rich sequence and an abundance of associated proteins that together form a dynamic cap that protects chromosome ends and allows them to be distinguished from deleterious DSBs. Telomere-associated proteins also function to regulate telomerase, the ribonucleoprtotein responsible for addition of the species-specific terminal repeat sequence. Loss of telomere function is an important mechanism for the chromosome instability commonly found in cancer. Dysfunctional telomeres can result either from alterations in the telomere-associated proteins required for end-capping function, or from alterations that promote the gradual or sudden loss of sufficient repeat sequence necessary to maintain proper telomere structure. Regardless of the mechanism, loss of telomere function can result in sister chromatid fusion and prolonged breakage/fusion/bridge (B/F/B) cycles, leading to extensive DNA amplification and large terminal deletions. B/F/B cycles terminate primarily when the unstable chromosome acquires a new telomere, most often by translocation of the ends of other chromosomes, thereby providing a mechanism for transfer of instability from one chromosome to another. Thus, the loss of a single telomere can result in on-going instability, affect multiple chromosomes, and generate many of the types of rearrangements commonly associated with human cancer.

Figure 1

Strand-specific CO-FISH detection of leading- (red) and lagging- (green) strand telomeres demonstrating chromosomal telomere-telomere fusion in a DNA-PKcs deficient background, indicative of end-capping failure owing to loss of structure, not loss of sequence.

Figure 2

CO-FISH detection of chromatid-type telomere fusions in TRF2 deficient cells demonstrating preferential failure of end-capping at leading-strand (red) telomeres.

Figure 3

B/F/B cycles as a mechanism for chromosome instability resulting from telomere loss. B/F/B cycles are initiated when sister chromatids fuse following the loss of a telomere. Owing to the presence of two centromeres, the fused sister chromatids break when the cell attempts to divide up its sister chromatids at anaphase. Because the break does not occur exactly at the site of the fusion, one daughter cell will receive a copy of the chromosome with an inverted repeat at its end, while the other daughter cell will have a copy of the chromosome with a terminal deletion. Owing to the lack of a telomere, these chromosomes will again undergo sister chromatid fusion after DNA replication, resulting in additional amplification and terminal deletions. The location of telomeres (squares), centromeres (circles) and orientation of the subtelomeric sequences (horizontal arrows) are shown.