Targeted Telomere Insertion Promotes Genome Instability in ALT Cancers

In most cancers, reactivation of telomerase maintains telomeres and prevents telomere-driven genome instability that occurs via the breakage-fusion-breakage cycle. However, a subset of tumors has been shown to maintain telomeres by a homologous recombination–dependent mechanism called alternative lengthening of telomeres (ALT). Previous studies have shown that, in addition to their normal binding sites throughout the genome, the NR2C/F class of orphan nuclear hormone receptors binds telomeric sequences in ALT cancers, but the function of these transcription factors in ALT remains unclear. Marzec and colleagues found that NR2C/F proteins directly bound to repeats of a variant telomeric motif specifically in ALT-positive cells. Binding of NR2C/F proteins to these motifs induced spatial proximity of their binding loci, facilitating telomere–telomere interactions necessary for homologous recombination during ALT. In addition, NR2C/F factors bridged telomeres and endogenous NR2C/F binding sites throughout the genome, bringing distant loci sufficiently close for recombination to occur and resulting in aberrant insertion of telomeric DNA sequences. This insertion of telomeric DNA occurred at a small subset of chromosomal NR2C/F binding sites in an NR2C/F-dependent process termed targeted telomere insertion (TTI). NR2C/F-mediated insertion of interstitial telomeric sequences was induced by genotoxic stress and generated potential common fragile sites and chromosomal translocations in ALT-positive cells. Importantly, analysis of 180 primary sarcomas, which exhibit a complex karyotype and are often ALT-positive, revealed frequent telomeric accumulation of NR2C/F proteins in ALT-positive tumors that increased with tumor grade. Together, these findings identify TTI as a mechanism of telomere-driven genome instability that is induced by ALT activation, and suggest that TTI may contribute to the complex chromosomal rearrangements observed in ALT-positive human sarcomas.

Marzec P, Armenise C, Pérot G, Roumelioti FM, Basyuk E, Gagos S, et al. Nuclear-receptor-mediated telomere insertion leads to genome instability in ALT cancers. Cell 2015;160:913–27.

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