Biology:ATRX
 Generic protein structure example |
Transcriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein (XNP) is a protein that in humans is encoded by the ATRX gene.[1][2][3]
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.[4] These interactions are important for maintaining silencing at these sites.[5][6][7]
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.[3]
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.[3]
Somatic mutations
Acquired mutations in ATRX have been reported in a number of human cancers including pancreatic neuroendocrine tumours,[8] gliomas,[9] astrocytomas,[10] osteosarcomas,[11] and malignant pheochromocytomas.[12] There is a strong correlation between ATRX mutations and an Alternative Lengthening of Telomeres (ALT) phenotype in cancers.[8]
Interactions
ATRX forms a complex with DAXX which is an histone H3.3 chaperone.[13]
ATRX has been also shown to interact with EZH2.[14]
See also
References
- ↑ "Cloning and characterization of a new human Xq13 gene, encoding a putative helicase". Human Molecular Genetics 3 (11): 1957–64. November 1994. doi:10.1093/hmg/3.11.1957. PMID 7874112.
- ↑ "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 51 (5): 1136–49. November 1992. PMID 1415255.
- ↑ 3.0 3.1 3.2 "Entrez Gene: ATRX alpha thalassemia/mental retardation syndrome X-linked (RAD54 homolog, S. cerevisiae)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=546.
- ↑ "ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells". Genome Research 20 (3): 351–60. March 2010. doi:10.1101/gr.101477.109. PMID 20110566.
- ↑ "ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes". Cell Reports 11 (3): 405–18. April 2015. doi:10.1016/j.celrep.2015.03.036. PMID 25865896.
- ↑ "Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells". Nature 522 (7555): 240–4. June 2015. doi:10.1038/nature14345. PMID 25938714. Bibcode: 2015Natur.522..240E.
- ↑ "Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres". Nucleic Acids Research 43 (21): 10227–37. December 2015. doi:10.1093/nar/gkv847. PMID 26304540.
- ↑ 8.0 8.1 "Altered telomeres in tumors with ATRX and DAXX mutations". Science 333 (6041): 425. July 2011. doi:10.1126/science.1207313. PMID 21719641. Bibcode: 2011Sci...333..425H.
- ↑ "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma". Nature 482 (7384): 226–31. January 2012. doi:10.1038/nature10833. PMID 22286061. Bibcode: 2012Natur.482..226S.
- ↑ "Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma". Oncotarget 3 (10): 1194–203. October 2012. doi:10.18632/oncotarget.689. PMID 23104868.
- ↑ "Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma". Cell Reports 7 (1): 104–12. April 2014. doi:10.1016/j.celrep.2014.03.003. PMID 24703847.
- ↑ Comino-Méndez, I (June 2016). "ATRX driver mutation in a composite malignant pheochromocytoma". Cancer Genetics 209 (6): 272–7. doi:10.1016/j.cancergen.2016.04.058. PMID 27209355.
- ↑ "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 107 (32): 14075–80. August 2010. doi:10.1073/pnas.1008850107. PMID 20651253. Bibcode: 2010PNAS..10714075L.
- ↑ "Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein". Human Molecular Genetics 7 (4): 679–84. April 1998. doi:10.1093/hmg/7.4.679. PMID 9499421.
Further reading
- "Nomenclature guidelines for X-linked mental retardation". American Journal of Medical Genetics 43 (1–2): 383–91. 1992. doi:10.1002/ajmg.1320430159. PMID 1605216.
- "ATRX and sex differentiation". Trends in Endocrinology and Metabolism 15 (7): 339–44. September 2004. doi:10.1016/j.tem.2004.07.006. PMID 15350606.
- "De novo and acquired forms of alpha thalassemia". Current Hematology Reports 5 (1): 11–4. March 2006. PMID 16537041.
- "Smith-Fineman-Myers syndrome in two brothers". American Journal of Medical Genetics 40 (4): 467–70. September 1991. doi:10.1002/ajmg.1320400419. PMID 1684092.
- "Linkage studies with the gene for an X-linked syndrome of mental retardation, microcephaly and spastic diplegia (MRX2)". American Journal of Medical Genetics 30 (1–2): 493–508. 1988. doi:10.1002/ajmg.1320300152. PMID 3177467.
- "RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression". Nucleic Acids Research 15 (17): 7155–74. September 1987. doi:10.1093/nar/15.17.7155. PMID 3658675.
- "Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome)". Cell 80 (6): 837–45. March 1995. doi:10.1016/0092-8674(95)90287-2. PMID 7697714.
- "Integration of gene maps: chromosome X". Genomics 22 (3): 590–604. August 1994. doi:10.1006/geno.1994.1432. PMID 8001970.
- "Cloning and expression of the murine homologue of a putative human X-linked nuclear protein gene closely linked to PGK1 in Xq13.3". Human Molecular Genetics 3 (1): 39–44. January 1994. doi:10.1093/hmg/3.1.39. PMID 8162050.
- "XNP mutation in a large family with Juberg-Marsidi syndrome". Nature Genetics 12 (4): 359–60. April 1996. doi:10.1038/ng0496-359. PMID 8630485.
- "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. September 1996. doi:10.1101/gr.6.9.791. PMID 8889548.
- "ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome". Human Molecular Genetics 5 (12): 1899–907. December 1996. doi:10.1093/hmg/5.12.1899. PMID 8968741.
- "A point mutation in the XNP gene, associated with an ATR-X phenotype without alpha-thalassemia". European Journal of Human Genetics 4 (6): 316–20. 1997. doi:10.1159/000472225. PMID 9043863.
- "Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase". Genomics 43 (2): 149–55. July 1997. doi:10.1006/geno.1997.4793. PMID 9244431.
- "Interaction of human recombination proteins Rad51 and Rad54". Nucleic Acids Research 25 (20): 4106–10. October 1997. doi:10.1093/nar/25.20.4106. PMID 9321665.
- "Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain". Nature Genetics 17 (2): 146–8. October 1997. doi:10.1038/ng1097-146. PMID 9326931.
- "Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein". Human Molecular Genetics 7 (4): 679–84. April 1998. doi:10.1093/hmg/7.4.679. PMID 9499421.
- "The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis". The Journal of Clinical Investigation 115 (2): 258–67. February 2005. doi:10.1172/JCI22329. PMID 15668733.
External links
- GeneReviews/NCBI/NIH/UW entry on Alpha-Thalassemia X-Linked Mental Retardation Syndrome; ATRX Syndrome; Alpha Thalassemia/Mental Retardation, X-Linked; XLMR-Hypotonic Face Syndrome
- OMIM entries on Alpha-Thalassemia X-Linked Mental Retardation Syndrome
- Human ATRX genome location and ATRX gene details page in the UCSC Genome Browser.
- Human RAD54L genome location and RAD54L gene details page in the UCSC Genome Browser.
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