Abstract
Telomeres are responsible for protecting chromosome ends in order to prevent the loss of coding DNA. Their maintenance is required for achieving immortality by neoplastic cells and can occur by upregulation of the telomerase enzyme or through a homologous recombination-associated process, the alternative lengthening of telomeres (ALT). The precise mechanisms that govern the activation of ALT or telomerase in tumor cells are not fully understood, although cellular origin may favor one of the other mechanisms that have been found thus far in mutual exclusivity. Specific mutational events influence ALT activation and maintenance: a unifying frequent feature of tumors that acquire this phenotype are the recurrent mutations of the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) or Death-Domain Associated Protein (DAXX) genes. This review summarizes the established criteria about this phenotype: its prevalence, theoretical molecular mechanisms and relation with ATRX, DAXX and other proteins (directly or indirectly interacting and resulting in the ALT phenotype).
Highlights
Telomeres are DNA–protein structures that protect chromosome ends, and consist of arrays containing guanine-rich (G-rich) repeats (TTAGGG)n in vertebrates
Genes 2016, 7, 66 observed in a telomerase-null mutant yeast, even-short telomeres 1 (EST1) [4]. These cells depend on a homologous recombination (HR) DNA-repair mechanism to maintain telomere length [4,5] and are characterized by the presence of: heterogeneous telomere lengths; the observation of alternative lengthening of telomeres (ALT)-associated promyelocytic leukemia bodies (APBs) that differ from common promyelocytic leukemia (PML) bodies found in other cell types by the inclusion of telomeric DNA and numerous specific recombination factors [6]; and telomere recombination with the presence of extrachromosomal telomeric repeats (ECTRs) [7]
Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene is localized in chromosome Xq21.1 and it encompasses 37 exons [66,67]
Summary
Telomeres are DNA–protein structures that protect chromosome ends, and consist of arrays containing guanine-rich (G-rich) repeats (TTAGGG)n in vertebrates. Genes 2016, 7, 66 observed in a telomerase-null mutant yeast, even-short telomeres 1 (EST1) [4] These cells depend on a homologous recombination (HR) DNA-repair mechanism to maintain telomere length [4,5] and are characterized by the presence of: heterogeneous telomere lengths; the observation of ALT-associated promyelocytic leukemia bodies (APBs) that differ from common promyelocytic leukemia (PML) bodies found in other cell types by the inclusion of telomeric DNA and numerous specific recombination factors [6]; and telomere recombination with the presence of extrachromosomal (linear and circular) telomeric repeats (ECTRs) [7]. We review the established notions and concepts about the ALT phenotype: its prevalence in cancer, the known molecular mechanisms and relation with ATRX, DAXX and other proteins that interact directly or indirectly with ALT
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