ATRX is an ATP-dependent chrX remodeler that functions as a central regulator of genome stability and chrX architecture 1. As the catalytic component of the ATRX:DAXX complex, it facilitates replication-independent deposition of histone H3.3 into repetitive heterochromatin regions including telomeres, pericentric heterochromatin, and retrotransposons 2. ATRX binds G-rich DNA sequences and quadruplex structures, stabilizing them into regular chrX by remodeling G4 DNA and incorporating H3.3-containing nucleosomes 1. The protein regulates chrX state through histone modifications, particularly H3K9me3 levels at zinc-finger genes, and maintains heterochromatin integrity through combinatorial readout of histone H3 methylation states 1. Clinically, ATRX mutations are among the most frequent in human cancers, particularly gliomas, where they drive pathogenesis through dysregulation of alternative lengthening of telomeres (ALT) 3. Pediatric glioblastoma frequently harbors H3.3-ATRX-DAXX pathway mutations (44% of cases), which correlate with aggressive tumor behavior and specific gene expression profiles 3. ATRX/DAXX mutations and ALT similarly associate with aggressive phenotypes in pancreatic neuroendocrine tumors and may serve as prognostic biomarkers 4. In developmental contexts, ATRX loss impairs oligodendrocyte differentiation and myelination through OPC-intrinsic effects, explaining white matter pathology in ATR-X intellectual disability syndrome 5.