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

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).

Keywords: ALT; ATRX; telomerase; telomeres.

Figure 1

Theoretical models for ALT mechanism: (A) Break-induced replication loss from the donor telomere (1 and 2 without loss from the donor telomere). In Model 3, there is a unidirectional replication fork with semi-conservative replication of the telomeres; (B) Unequal telomeric sister chromatid exchange (T-SCE) model; (C) Rolling circle and t-circle formation after t-loop resolution providing a linear double strand break for subsequent HR-mediated activation into the homologous templates. Adapted from [62].

Figure 2

A proposed theoretical mechanism for Alpha Thalassemia/Mental Retardation Syndrome X-Linked/Death-Domain Associated Protein (ATRX/DAXX) chromatin landscaping: ATRX binds to histone H3 at heterochromatin through interaction of its ATRX-DNMT3-DNMT3L (ADD) domain with an H3 N-terminal tail, trimethylated at Lys9 (H3K9me3) and unmodified at Lys4 (H3K4me0). HP1 also recognizes H3K9me3, boosting this recruitment. Once in its target site, ATRX, in combination with DAXX, facilitates the deposition of the histone variant H3.3 [80]. The deposition of H3.3 leads to changes in chromatin that prevent the formation of G4-DNA structures. HP1: heterochromatin protein 1.