The first molecular details of ALT in human tumor cells

Abstract

The activation of a telomere maintenance mechanism (TMM) is indispensable for cellular immortalization, a hallmark of human cancer. Although most human cancers use telomerase as their TMM, some use an alternative lengthening of telomeres (ALT) mechanism. The latter especially include specific subtypes of soft tissue sarcomas where ALT occurs most often in tumors with complex karyotypes, astrocytic brain tumors and osteosarcomas. The prognostic significance of ALT varies according to the type of tumor. Some ALT cells have atypical features, suggesting the possibility that there is more than one ALT mechanism. ALT cells are characterized by instability at a specific minisatellite locus (although they are stable at microsatellite loci) and by high rates of telomeric recombinational exchange. We propose a revised model whereby unequal telomeric exchange and asymmetrical chromosome segregation could result in telomere length maintenance in a cell population. In at least some ALT cells, telomere maintenance requires the integrity of the MRN (MRE11-RAD50-NBS1) recombination complex and is efficiently repressed by its sequestration. Microsatellite instability (MSI) often results in disruption of MRN, so ALT may usually be incompatible with MSI. We suggest that ALT in human tumors is a dysregulated version of an aspect of normal mammalian telomere homeostasis, which may be a vestige of the TMM used by ancient eukaryotes. Understanding the molecular basis of ALT has important implications for the diagnosis and treatment of tumors that use this TMM.

The significance of telomeric aggregates in the interphase nuclei of tumor cells

“…It was shown that telomeres in tumor cells commonly manifest telomere dysfunction, and chromosomal aberrations indicative of these defects are observed. Telomerase is activated in 85% of the tumors, while it is not present in the rest of the tumors, some of which have demonstrated alternative lengthening of telomeres (ALT) [Muntoni and Reddel, 2005].…”

Epigenetic regulation of telomeres in human cancer

“…Telomerase is a reverse transcriptase that synthetizes telomere repeats de novo at the chromosome ends (reviewed in Blackburn, 2001;Collins and Mitchell, 2002;Blasco, 2005) and in this way regulates the length of telomeric repeats. An alternative mechanism for telomere elongation is the so-called alternative lengthening of telomeres or ALT mechanism (reviewed in Muntoni and Reddel, 2005), which relies on homologous recombination events at telomeres (Dunham et al, 2000;Bailey et al, 2004;Bechter et al, 2004). ALT cells are characterized by long and heterogeneous telomeres, increased telomere recombination frequencies, as well as by the colocalization of telomeres with the PML bodies forming the so-called ALT-associated PML bodies or APBs (reviewed in Dunham et al, 2000;Bechter et al, 2004;Bailey et al, 2004;Muntoni and Reddel, 2005).…”

“…An alternative mechanism for telomere elongation is the so-called alternative lengthening of telomeres or ALT mechanism (reviewed in Muntoni and Reddel, 2005), which relies on homologous recombination events at telomeres (Dunham et al, 2000;Bailey et al, 2004;Bechter et al, 2004). ALT cells are characterized by long and heterogeneous telomeres, increased telomere recombination frequencies, as well as by the colocalization of telomeres with the PML bodies forming the so-called ALT-associated PML bodies or APBs (reviewed in Dunham et al, 2000;Bechter et al, 2004;Bailey et al, 2004;Muntoni and Reddel, 2005). Telomerase is undetectable in most somatic tissues with the exception of stem cell compartments and some highly proliferative cell types (reviewed in Flores et al, 2006), where telomerase levels are not sufficient to prevent the progressive telomere shortening associated with age (Harley et al, 1990;Canela et al, 2007).…”

“…In contrast, more than 90% of all types of human tumors have high levels of telomerase activity, where is thought to maintain a minimum length of telomere repeats to sustain tumor growth (reviewed in Shay and Wright, 2006). Interestingly, those tumors that are telomerase-negative, activate ALT mechanisms (reviewed in Muntoni and Reddel, 2005), highlighting the importance of telomere length maintenance in cancer growth. Although the mechanisms by which telomerase is upregulated in cancer are starting to be unveiled and generally involve altered expression of oncogenes and tumor suppressor genes (reviewed in Flores et al, 2006;Shay and Wright, 2006), virtually nothing is known on the mechanisms that activate ALT in cancer cells.…”

“…A significant correlation between subtelomeric DNA repeat hypomethylation and telomere recombination in human cancer Telomeres can be elongated either by telomerase or by the recombination-based ALT mechanism (Muntoni and Reddel, 2005). To address whether DNA methylation changes in human normal and cancer cell lines correlated with telomere recombination frequencies, we determined the frequency of telomeric sister chromatid exchange (T-SCE) events in the different cell lines studied here using chromosome orientation FISH (CO-FISH) on metaphase spreads (Materials and methods section; Figure 7a for quantification and Figure 7b for representative examples), previously shown to reflect on homologous recombination between telomeric repeats (Bailey et al, 2004;Bechter et al, 2004;Gonzalo et al, 2006).…”