Fig 1.
Schematic representation of the ATRX protein showing its major functional domains.
The N-terminal ADD domain, containing GATA-like and PHD-like domains, mediates chromatin localization and binding [1,2]. A neuronal MECP2 (nMECP2) binding domain provides an alternative route for ATRX recruitment to chromatin targets [2]. The unstructured central region harbors “SDT-like” domains, which modulate MRN activity, and a DAXX-binding domain essential for DAXX-mediated heterochromatin regulation [3]. Towards the C-terminus, the SNF2 ATPase/helicase domain promotes chromatin remodeling. Additional features include an EZH2 domain, which supports PRC2-associated histone methylation, and an HP1α binding domain, facilitating heterochromatin recognition and PML nuclear body interactions [1,2].
Fig 2.
Overview of known molecular pathways of ATRX.
The ATRX/DAXX complex localizes to PML nuclear bodies, where it is recruited to telomeres, pericentromeric heterochromatin, and other DNA repeat regions. This recruitment is facilitated by HP1α, which recognizes H3K9me3 marks, allowing ATRX/DAXX to deposit histone H3.3 and maintain heterochromatin integrity [1,2,4,5,6]. ATRX also forms a complex with EZH2 and is incorporated into the larger PRC2 complex, interacting with Xist lncRNA to promote X chromosome inactivation during early female embryonic development [1,2]. In addition, ATRX sequesters the MRN complex from telomeric regions, preserving telomere stability [2]. Beyond its role in heterochromatin maintenance, ATRX modulates replacement of histone macroH2A from gene loci, thereby maintaining a euchromatic state at target genes, including those encoding α-globin and tankyrase, and thus supporting their transcription. ATRX is also implicated in the DNA damage response at stalled replication forks through multiple mechanisms. It indirectly reduces telomere cohesion and telomere sister chromatid exchanges (T-SCEs) by regulating tankyrase, which in turn decreases transcription of TERRA, a long noncoding RNA (lncRNA) originating from telomeric DNA. Excess TERRA promotes secondary structures such as G-quadruplexes (G4) and R-loops that can stall replication forks [2,7–12]. ATRX helps sequester TERRA and participates in resolving these secondary structures, although its precise mechanism of action remains to be fully elucidated. Influenced and adapted from [1,2].
Fig 3.
Summary of the effects of ATRX mutations on disease, tumors, and development. Mutations in conserved ATRX domains impair α-globin transcription, leading to α-thalassemia. Germline mutations of these domains induce the development of ATR-X syndrome. Mutations to ATRX in gliomas have been observed to inhibit production of DRG2 and RPRM, proteins critical for regulation of the G2M checkpoint [2,16,17]. IDH1R132H+ gliomas with ATRX mutations exhibit BRD3/4-dependent immune escape, which involves elevated PD-L expression and increased production of cytokines. including but not limited to CXCL, CSF2, IL-6, IL-8, and IL-33. This culminates with increased recruitment of M2 macrophages and T-cell exhaustion, facilitating immune escape [1,18,19]. ATRX loss increases dsRNA production, activating a signaling cascade through RIG1, MDA-5, STAT1, and ISG15 that boosts type I interferon and cytokine output, ultimately enhancing recruitment of CD3+ and CD4 + T cells and increasing innate immunity sensitization [1,18]. Disruption of ATRX/EZH2 complex formation reduces suppression of FADD production, allowing FADD-mediated PARP sequestration and heightening sensitivity to temozolomide (TMZ) [2,20,21]. In PanNETs, ATRX-DAXX-MEN1 (A-D-M) mutations hypermethylate CpG islands at PDX1 gene loci, compromising β-cell function [1,2,22]. Loss of ATRX is also a common driver of the ALT (alternative lengthening of telomeres) phenotype, which features APB (ALT-associated PML bodies) formation, increased telomeric sister chromatid exchanges (T-SCEs), accumulation of extrachromosomal C-circles, and heightened TERRA-induced G-quadruplex and R-loop formation [1,2,10–12]. Finally, ATRX dysfunction has been proposed to influence early bone development by downregulating CART, thereby reducing osteoclast activity and increasing trabecular bone formation [23]. Influenced and adapted from [1,2].
Table 1.
Reviews of ATRX in other tumours.
Fig 4.
Identification and selection of studies via databases.
Table 2.
Characteristics of included publications examining the prevalence of ATRX loss in human pituitary neuroendocrine tumours.
Table 3.
Demographic and clinical patient data examined in the included publications.
Table 4.
Quality assessment using the Joanna Briggs Institute (JBI) critical appraisal checklist for prevalence studies.
Table 5.
The Joanna Briggs Institute (JBI) critical appraisal checklist for risk of bias for case reports that were identified.
Table 6.
Demographic and histopathological characteristics of tumours exhibiting ATRX.
Table 7.
Fisher’s exact tests comparing ATRX expression status and tumour recurrence (A), tumour hormone secretion type (B), and sex of patient (C).