ATRX and DAXX: Mechanisms and Mutations

Abstract

Recent genome sequencing efforts in a variety of cancers have revealed mutations and/or structural alterations in ATRX and DAXX, which together encode a complex that deposits histone variant H3.3 into repetitive heterochromatin. These regions include retrotransposons, pericentric heterochromatin, and telomeres, the latter of which show deregulation in ATRX/DAXX-mutant tumors. Interestingly, ATRX and DAXX mutations are often found in pediatric tumors, suggesting a particular developmental context in which these mutations drive disease. Here we review the functions of ATRX and DAXX in chromatin regulation as well as their potential contributions to tumorigenesis. We place emphasis on the chromatin remodeler ATRX, which is mutated in the developmental disorder for which it is named, α-thalassemia, mental retardation, X-linked syndrome, and at high frequency in a number of adult and pediatric tumors.

Figure 1.

Mutations identified in ATRX syndrome and a subset of cancers. (A) Schematic summarizing that the mutations identified in patients with ATRX syndrome are concentrated in the ADD and SNF2_N helicase domains. Mutations are represented by a black needle; larger needle head size and height indicate larger mutation frequency. (B) Needle plot depicting the distribution of mutations identified in GBM (glioblastoma multiforme), LGG (low-grade glioma), and NB (neuroblastoma) along the ATRX protein product (Gonzalez-Perez et al. 2013). The needles’ head size and height indicate mutational recurrence. Note that these mutations are present throughout the gene locus and not concentrated at one particular domain. Blue bars below protein product represent in-frame fusions identified in NB (Cheung et al. 2012).

Figure 2.

ATRX has multiple functions in the chromatin landscape. (A) The SWI/SNF-like chromatin remodeler ATRX is found in various complexes throughout the chromosome to maintain distinct chromatin states. (B) Model summarizing ATRX’s roles in the epigenetic landscape. (Left) ATRX has chromatin remodeling function to bind and regulate genomic regions enriched for H3K9me3 via its ADD domain and HP1α. It also recruits EZH2 to deposit H3K27me3 to regulate transcription. (Right) ATRX functions to negatively regulate macroH2A (mH2a) deposition at the α-globin locus and telomeres and is critical in H3.3 deposition along with DAXX, particularly at repetitive regions (e.g., telomeres). (Center) ATRX also binds DNA through its SNF2_N helicase domain to resolve tandem repeats to promote transcription at the α-globin locus.