Abstract
Proper telomeric chromatin configuration is thought to be essential for telomere homeostasis and stability. Previous studies in mouse suggested that loss of heterochromatin marks at telomeres might favor onset of Alternative Lengthening of Telomeres (ALT) pathway, by promoting homologous recombination. However, analysis of chromatin status at human ALT telomeres has never been reported. Here, using isogenic human cell lines and cellular hybrids, which rely either on telomerase or ALT to maintain telomeres, we show that chromatin compaction is reduced at ALT telomeres and this is associated with a global decrease in telomeric H3K9me3. This, subsequently, leads to upregulation of telomere transcription. Accordingly, restoration of a more condensed telomeric chromatin through telomerase-dependent elongation of short ALT telomeres reduces telomere transcription. We further show that loss of ATRX chromatin remodeler function, a frequent characteristic of ALT cells, is not sufficient to decrease chromatin condensation at telomeres nor to increase the expression of telomeric RNA species. These results offer new insight on telomeric chromatin properties in ALT cells and support the hypothesis that telomeric chromatin decondensation is important for ALT pathway.
Highlights
Telomeres are specialized structures that protect the ends of chromosomes from degradation and fusion [1]
The Alternative Lengthening of Telomeres (ALT) phenotype of SI24 was confirmed by the presence of (i) extrachromosomal telomeric repeat (ECTR) species, among which C-circles are readily detectable [30] (Figure 1G), and (ii) associated Promyelocytic leukemia (PML) bodies (APBs), revealed by the colocalization of TRF2 and Promyelocytic leukemia (PML) proteins (Figure 1H)
Agreeing with recent reports of orphan receptor binding at ALT telomeres [4,5], we showed the presence of COUP-TF2 at telomeres of both IMRB and SI24 ALT cell lines (Figure 1I)
Summary
Telomeres are specialized structures that protect the ends of chromosomes from degradation and fusion [1]. Unlimited replication potential is conferred to cells that activate a telomere maintenance mechanism (TMM) This TMM is dependent on either telomerase, a reverse transcriptase adding telomeric repeats at chromosome ends, or on one or more so-called ‘ALT’ (Alternative Lengthening of Telomeres) mechanism(s), still poorly understood but known to rely on telomeric homologous recombinations [2]. With respect to emerging anti-cancer therapies targeting telomere maintenance, it is crucial to get a better understanding of ALT mechanism [6]. In this view, identifying structural differences between telomerase- and ALT-dependent telomeres is likely to provide useful information
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