Epigenetic Characteristics of Human Subtelomeres Vary in Cells Utilizing the Alternative Lengthening of Telomeres (ALT) Pathway

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 repr...

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Published inLife (Basel, Switzerland) Vol. 11; no. 4; p. 278
Main Authors Toubiana, Shir, Tzur-Gilat, Aya, Selig, Sara
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 26.03.2021
MDPI
Subjects
alternative lengthening of telomeres (ALT)
Antibiotics
Cancer
Cell division
Cell lines
Chromosomes
Deoxyribonucleic acid
DNA
DNA methylation
DNA polymerase
Enzymes
Epigenetics
Fibroblasts
Gene expression
Genetic testing
H3K4me3
Histones
Immortalization
Recombination
Senescence
subtelomere
Telomerase
telomere
Telomeres
TERRA
United States > US
TERRA
alternative lengthening of telomeres (ALT)
H3K4me3
H3K9me3
telomere
DNA methylation
subtelomere
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Summary: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.
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Both authors contributed equally.
ISSN:2075-1729
2075-1729
DOI:10.3390/life11040278