Abstract
Most human cancers circumvent senescence by activating a telomere length maintenance mechanism, most commonly involving telomerase activation. A minority of cancers utilize the recombination-based alternative lengthening of telomeres (ALT) pathway. The exact requirements for unleashing normally repressed recombination at telomeres are yet unclear. Epigenetic modifications at telomeric regions were suggested to be pivotal for activating ALT; however, conflicting data exist regarding their exact nature and necessity. To uncover common ALT-positive epigenetic characteristics, we performed a comprehensive analysis of subtelomeric DNA methylation, histone modifications, and TERRA expression in several ALT-positive and ALT-negative cell lines. We found that subtelomeric DNA methylation does not differentiate between the ALT-positive and ALT-negative groups, and most of the analyzed subtelomeres within each group do not share common DNA methylation patterns. Additionally, similar TERRA levels were measured in the ALT-positive and ALT-negative groups, and TERRA levels varied significantly among the members of the ALT-positive group. Subtelomeric H3K4 and H3K9 trimethylation also differed significantly between samples in the ALT-positive group. Our findings do not support a common route by which epigenetic modifications activate telomeric recombination in ALT-positive cells, and thus, different therapeutic approaches will be necessary to overcome ALT-dependent cellular immortalization.
Highlights
Telomeres are structures that cap all eukaryotic chromosome ends
To examine whether certain epigenetic properties are common for all cell lines that activate the alternative lengthening of telomeres (ALT) pathway for telomere maintenance, we studied seven ALT+ cell lines, of which five were established from tumors, and two were generated from normal fibroblasts by chemical or SV40 transformation [40] (Table 1)
DNMT3B is a DNA methyltransferases (DNMT) that targets repetitive regions, among them subtelomeres, and its loss of function leads to subtelomeric hypomethylation in ICF1 syndrome [31,43]
Summary
Telomeres are structures that cap all eukaryotic chromosome ends. Human telomericDNA at birth consists of approximately 12 kb of TTAGGG repeats [1], complexed mainly with the protective Shelterin proteins [2]. Telomeres are structures that cap all eukaryotic chromosome ends. Human telomeres shorten continuously with each cell division, and when they reach a critically short length, cells enter senescence [3]. Telomere length-associated senescence, termed as replicative senescence, fulfills a tumor-suppressing function, since shortening beyond a critically short length in cells with properly functioning cellular checkpoints, results in chromosome ends recognized as double-strand DNA breaks (DSB) [4]. Continuous cell divisions in the presence of critically short telomeres, as occurs frequently during malignant transformation, induce chromosome end fusions that lead to major genomic instability, one of the hallmarks of cancer [5]. The vast majority of human cancers activate a mechanism that ensures telomere length maintenance
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