The Role of ATRX in the Alternative Lengthening of Telomeres (ALT) Phenotype

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).