Alternative lengthening of telomeres: remodeling the telomere architecture

Abstract

To escape from the normal limits on proliferative potential, cancer cells must employ a means to counteract the gradual telomere attrition that accompanies semi-conservative DNA replication. While the majority of human cancers do this by up-regulating telomerase enzyme activity, most of the remainder use a homologous recombination-mediated mechanism of telomere elongation known as alternative lengthening of telomeres (ALT). Many molecular details of the ALT pathway are unknown, and even less is known regarding the mechanisms by which this pathway is activated. Here, we review current findings about telomere structure in ALT cells, including DNA sequence, shelterin content, and heterochromatic state. We speculate that remodeling of the telomere architecture may contribute to the emergence and maintenance of the ALT phenotype.

Keywords: DNA damage response (DDR); alternative lengthening of telomeres (ALT); chromatin; nuclear receptors; recombination; shelterin; telomere; variant telomeric repeats.

FIGURE 1

HR-mediated telomeric replication in ALT cells. Non-canonical sequences are present in the proximal 2 kb region of the telomere array in human cells. Telomeric replication in ALT cells can occur by HR-mediated inter-telomeric copying of (A) canonical TTAGGG repeats in the telomere repeat array, or (B) variant or non-canonical repeats present in the proximal regions of the telomere.

FIGURE 2

Remodeling of the telomere architecture during activation of the ALT mechanism. Non-canonical repeat sequences existing in the proximal region are distributed throughout the telomere array during ALT activation (see Figure 1). Hence, there is an insufficient concentration of shelterin binding sites for telomere capping, causing the telomere to elicit a DDR, whilst still being able to suppress chromosomal end-to-end fusions caused by NHEJ. DNA-binding proteins capable of binding specifically to these non-canonical sequences are consequently spread throughout the telomere, increasing its recombinogenicity. These proteins may also be capable of recruiting various chromatin remodeling complexes which can alter the telomere architecture further, in favor of telomeric recombination.