ATRX

Function

Transcriptional regulator ATRX contains an ATPase / helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. ATRX is required for deposition of the histone variant H3.3 at telomeres and other genomic repeats. These interactions are important for maintaining silencing at these sites.

In addition, ATRX undergoes cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis.

Clinical significance

Inherited mutations

Inherited mutations of the ATRX gene are associated with an X-linked mental retardation (XLMR) syndrome most often accompanied by alpha-thalassemia (ATR-X) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported. Female carriers may demonstrate skewed X chromosome inactivation.

Somatic mutations

Acquired mutations in ATRX have been reported in a number of human cancers including pancreatic neuroendocrine tumours, gliomas, osteosarcomas, soft-tissue sarcomas, and malignant pheochromocytomas. There is a strong correlation between ATRX mutations and an Alternative Lengthening of Telomeres (ALT) phenotype in cancers.

Interactions

ATRX forms a complex with DAXX which is an histone H3.3 chaperone.

ATRX has been also shown to interact with EZH2.

References

References

1. (June 2016). "ATRX driver mutation in a composite malignant pheochromocytoma". Cancer Genetics.
2. (November 2017). "Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas". Cell.
3. (April 1998). "Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein". Human Molecular Genetics.
4. (April 2014). "Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma". Cell Reports.
5. (June 2015). "Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells". Nature.
6. "Entrez Gene: ATRX alpha thalassemia/mental retardation syndrome X-linked (RAD54 homolog, S. cerevisiae)".
7. (November 1992). "X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21.31 by X inactivation and linkage analysis". American Journal of Human Genetics.
8. (July 2011). "Altered telomeres in tumors with ATRX and DAXX mutations". Science.
9. (October 2012). "Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma". Oncotarget.
10. (August 2010). "Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres". Proceedings of the National Academy of Sciences of the United States of America.
11. (January 2012). "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma". Nature.
12. (November 1994). "Cloning and characterization of a new human Xq13 gene, encoding a putative helicase". Human Molecular Genetics.
13. (December 2015). "Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres". Nucleic Acids Research.
14. (April 2015). "ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes". Cell Reports.
15. (March 2010). "ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells". Genome Research.