ATRX represses alternative lengthening of telomeres

Abstract

The unlimited proliferation of cancer cells requires a mechanism to prevent telomere shortening. Alternative Lengthening of Telomeres (ALT) is an homologous recombination-mediated mechanism of telomere elongation used in tumors, including osteosarcomas, soft tissue sarcoma subtypes, and glial brain tumors. Mutations in the ATRX/DAXX chromatin remodeling complex have been reported in tumors and cell lines that use the ALT mechanism, suggesting that ATRX may be an ALT repressor. We show here that knockout or knockdown of ATRX in mortal cells or immortal telomerase-positive cells is insufficient to activate ALT. Notably, however, in SV40-transformed mortal fibroblasts ATRX loss results in either a significant increase in the proportion of cell lines activating ALT (instead of telomerase) or in a significant decrease in the time prior to ALT activation. These data indicate that loss of ATRX function cooperates with one or more as-yet unidentified genetic or epigenetic alterations to activate ALT. Moreover, transient ATRX expression in ALT-positive/ATRX-negative cells represses ALT activity. These data provide the first direct, functional evidence that ATRX represses ALT.

Alternative lengthening of telomeres does exist in various canine sarcomas

“…DAXX and ATRX are both important for homologous recombination by impairing the heterochromatic state of telomeres . It has been shown that ATRX expression represses ALT activity and in human cancer loss of ATRX is reported as another ALT feature . We found a loss of ATRX expression in all ALT‐positive canine tumor samples whereas all but two other analyzed ALT‐negative tumors did express ATRX.…”

Differential nuclear ATRX expression in sarcomas

“…Therefore, the current understanding is that ATRX mutations rather provoke ALT, but additional genetic or epigenetic changes are probably required to activate the ALT pathway fully . Nevertheless, it has been shown recently that transient restoration of ATRX expression repressed the ALT phenotype in ALT‐positive/ATRX negative cells of mesenchymal origin . Thus, further studies are needed to uncover comprehensively the underlying molecular mechanisms leading to ALT in tumours lacking nuclear ATRX expression.…”

Stop pulling my strings — what telomeres taught us about the DNA damage response

“…A strong candidate is the histone chaperone ATRX, which is mutated in a large majority of cells and tumours that exploit the ALT pathway 110,111 . Reintroducing ATRX into ALT cells suppresses T-SCE, APB and c-circle formation, and inter-chromosomal telomeric recombination 112,113 (FIG. 3c).…”

“…Taken together, these studies suggest that both the helicase-unwinding activity of ATRX and the histone chaperone properties of the ATRX–DAXX complex are likely to counteract telomere recombination by resolving stable secondary structures that would otherwise impede fork progression. It is important to emphasize that ATRX depletion by itself is not sufficient to induce ALT 112,113 , indicating that additional genetic alteration(s) are necessary. Interestingly, deletion of the gene encoding the histone chaperone ASF1A is sufficient to trigger ALT-like phenotypes in telomerase-positive cells 120 , and binding of the nucleosome-remodelling deacetylase (NuRD) complex to variant repeats found at telomeres in ALT cells creates a permissive environment for recombination 121 .…”