ATRX

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.[5][6][7]

ATRX
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2JM1, 2LBM, 2LD1, 3QL9, 3QLA, 3QLC, 3QLN, 4W5A
Identifiers
Aliases	ATRX, ATR2, JMS, MRXHF1, RAD54, RAD54L, SFM1, SHS, XH2, XNP, ZNF-HX, MRX52, alpha thalassemia/mental retardation syndrome X-linked, chromatin remodeler, ATRX chromatin remodeler
External IDs	OMIM: 300032 MGI: 103067 HomoloGene: 416 GeneCards: ATRX
Gene location (Human) Chr. X chromosome (human)[1] Band Xq21.1 Start 77,504,878 bp[1] End 77,786,233 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X D|X 47.26 cM Start 105,797,615 bp[2] End 105,929,403 bp[2]
Gene ontology Molecular function • DNA binding • nucleotide binding • chromo shadow domain binding • GO:0008026 helicase activity • histone binding • metal ion binding • DNA translocase activity • methylated histone binding • GO:0004003 DNA helicase activity • GO:0001948 protein binding • hydrolase activity • ATP binding • chromatin binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • PML body • nuclear subtelomeric heterochromatin • SWI/SNF superfamily-type complex • pericentric heterochromatin • chromosome • nuclear heterochromatin • heterochromatin • nuclear chromosome • chromosome, telomeric region • nuclear chromosome, telomeric region • condensed nuclear chromosome, centromeric region • cell nucleus • nucleoplasm • nuclear body • nuclear pericentric heterochromatin Biological process • chromatin remodeling • nucleosome assembly • DNA recombination • post-embryonic forelimb morphogenesis • regulation of transcription, DNA-templated • multicellular organism growth • DNA damage response, signal transduction by p53 class mediator • positive regulation of nuclear cell cycle DNA replication • Sertoli cell development • transcription, DNA-templated • protein localization to chromosome, telomeric region • cellular response to DNA damage stimulus • positive regulation of telomeric RNA transcription from RNA pol II promoter • positive regulation of telomere maintenance • DNA methylation • negative regulation of telomeric RNA transcription from RNA pol II promoter • seminiferous tubule development • spermatogenesis • replication fork processing • negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric • DNA replication-independent nucleosome assembly • forebrain development • DNA repair • cellular response to hydroxyurea • positive regulation of transcription from RNA polymerase II promoter • DNA duplex unwinding • regulation of histone H3-K9 trimethylation • GO:0043147 meiotic spindle organization • chromosome organization involved in meiotic cell cycle • chromatin organization Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	546	22589
Ensembl	ENSG00000085224	ENSMUSG00000031229
UniProt	P46100	Q61687
RefSeq (mRNA)	NM_000489 NM_138270 NM_138271	NM_009530
RefSeq (protein)	NP_000480 NP_612114	NP_033556
Location (UCSC)	Chr X: 77.5 – 77.79 Mb	Chr X: 105.8 – 105.93 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[8] These interactions are important for maintaining silencing at these sites.[9][10][11]

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.[7]

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.[7]

Somatic mutations

Acquired mutations in ATRX have been reported in a number of human cancers including pancreatic neuroendocrine tumours,[12] gliomas,[13] astrocytomas,[14] osteosarcomas,[15] and malignant pheochromocytomas.[16] There is a strong correlation between ATRX mutations and an Alternative Lengthening of Telomeres (ALT) phenotype in cancers.[12]

Interactions

ATRX forms a complex with DAXX which is an histone H3.3 chaperone.[17]

ATRX has been also shown to interact with EZH2.[18]

See also

• Alpha-thalassemia mental retardation syndrome

References

1. GRCh38: Ensembl release 89: ENSG00000085224 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031229 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Stayton CL, Dabovic B, Gulisano M, Gecz J, Broccoli V, Giovanazzi S, et al. (November 1994). "Cloning and characterization of a new human Xq13 gene, encoding a putative helicase". Human Molecular Genetics. 3 (11): 1957–64. doi:10.1093/hmg/3.11.1957. PMID 7874112.
6. Gibbons RJ, Suthers GK, Wilkie AO, Buckle VJ, Higgs DR (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. 51 (5): 1136–49. PMC 1682840. PMID 1415255.
7. "Entrez Gene: ATRX alpha thalassemia/mental retardation syndrome X-linked (RAD54 homolog, S. cerevisiae)".
8. Wong LH, McGhie JD, Sim M, Anderson MA, Ahn S, Hannan RD, et al. (March 2010). "ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells". Genome Research. 20 (3): 351–60. doi:10.1101/gr.101477.109. PMC 2840985. PMID 20110566.
9. Voon HP, Hughes JR, Rode C, De La Rosa-Velázquez IA, Jenuwein T, Feil R, et al. (April 2015). "ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes". Cell Reports. 11 (3): 405–18. doi:10.1016/j.celrep.2015.03.036. PMC 4410944. PMID 25865896.
10. Elsässer SJ, Noh KM, Diaz N, Allis CD, Banaszynski LA (June 2015). "Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells". Nature. 522 (7555): 240–4. doi:10.1038/nature14345. PMC 4509593. PMID 25938714.
11. Udugama M, M Chang FT, Chan FL, Tang MC, Pickett HA, R McGhie JD, et al. (December 2015). "Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres". Nucleic Acids Research. 43 (21): 10227–37. doi:10.1093/nar/gkv847. PMC 4666390. PMID 26304540.
12. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, et al. (July 2011). "Altered telomeres in tumors with ATRX and DAXX mutations". Science. 333 (6041): 425. doi:10.1126/science.1207313. PMC 3174141. PMID 21719641.
13. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. (January 2012). "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma". Nature. 482 (7384): 226–31. doi:10.1038/nature10833. PMID 22286061.
14. Kannan K, Inagaki A, Silber J, Gorovets D, Zhang J, Kastenhuber ER, et al. (October 2012). "Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma". Oncotarget. 3 (10): 1194–203. doi:10.18632/oncotarget.689. PMC 3717947. PMID 23104868.
15. Chen X, Bahrami A, Pappo A, Easton J, Dalton J, Hedlund E, et al. (April 2014). "Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma". Cell Reports. 7 (1): 104–12. doi:10.1016/j.celrep.2014.03.003. PMC 4096827. PMID 24703847.
16. 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.
17. Lewis PW, Elsaesser SJ, Noh KM, Stadler SC, Allis CD (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. 107 (32): 14075–80. doi:10.1073/pnas.1008850107. PMC 2922592. PMID 20651253.
18. Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L (April 1998). "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. doi:10.1093/hmg/7.4.679. PMID 9499421.

Further reading

• Mulley JC, Kerr B, Stevenson R, Lubs H (1992). "Nomenclature guidelines for X-linked mental retardation". American Journal of Medical Genetics. 43 (1–2): 383–91. doi:10.1002/ajmg.1320430159. PMID 1605216.
• Tang P, Park DJ, Marshall Graves JA, Harley VR (September 2004). "ATRX and sex differentiation". Trends in Endocrinology and Metabolism. 15 (7): 339–44. doi:10.1016/j.tem.2004.07.006. PMID 15350606.
• Forget BG (March 2006). "De novo and acquired forms of alpha thalassemia". Current Hematology Reports. 5 (1): 11–4. PMID 16537041.
• Adès LC, Kerr B, Turner G, Wise G (September 1991). "Smith-Fineman-Myers syndrome in two brothers". American Journal of Medical Genetics. 40 (4): 467–70. doi:10.1002/ajmg.1320400419. PMID 1684092.
• Sutherland GR, Gedeon AK, Haan EA, Woodroffe P, Mulley JC (1988). "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. doi:10.1002/ajmg.1320300152. PMID 3177467.
• Shapiro MB, Senapathy P (September 1987). "RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression". Nucleic Acids Research. 15 (17): 7155–74. doi:10.1093/nar/15.17.7155. PMC 306199. PMID 3658675.
• Gibbons RJ, Picketts DJ, Villard L, Higgs DR (March 1995). "Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome)". Cell. 80 (6): 837–45. doi:10.1016/0092-8674(95)90287-2. PMID 7697714.
• Wang LH, Collins A, Lawrence S, Keats BJ, Morton NE (August 1994). "Integration of gene maps: chromosome X". Genomics. 22 (3): 590–604. doi:10.1006/geno.1994.1432. PMID 8001970.
• Gecz J, Pollard H, Consalez G, Villard L, Stayton C, Millasseau P, Khrestchatisky M, Fontes M (January 1994). "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. doi:10.1093/hmg/3.1.39. PMID 8162050.
• Villard L, Gecz J, Mattéi JF, Fontés M, Saugier-Veber P, Munnich A, Lyonnet S (April 1996). "XNP mutation in a large family with Juberg-Marsidi syndrome". Nature Genetics. 12 (4): 359–60. doi:10.1038/ng0496-359. PMID 8630485.
• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Picketts DJ, Higgs DR, Bachoo S, Blake DJ, Quarrell OW, Gibbons RJ (December 1996). "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. doi:10.1093/hmg/5.12.1899. PMID 8968741.
• Villard L, Lacombe D, Fontés M (1997). "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. doi:10.1159/000472225. PMID 9043863.
• Villard L, Lossi AM, Cardoso C, Proud V, Chiaroni P, Colleaux L, Schwartz C, Fontés M (July 1997). "Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase". Genomics. 43 (2): 149–55. doi:10.1006/geno.1997.4793. PMID 9244431.
• Golub EI, Kovalenko OV, Gupta RC, Ward DC, Radding CM (October 1997). "Interaction of human recombination proteins Rad51 and Rad54". Nucleic Acids Research. 25 (20): 4106–10. doi:10.1093/nar/25.20.4106. PMC 147015. PMID 9321665.
• Gibbons RJ, Bachoo S, Picketts DJ, Aftimos S, Asenbauer B, Bergoffen J, Berry SA, Dahl N, Fryer A, Keppler K, Kurosawa K, Levin ML, Masuno M, Neri G, Pierpont ME, Slaney SF, Higgs DR (October 1997). "Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain". Nature Genetics. 17 (2): 146–8. doi:10.1038/ng1097-146. PMID 9326931.
• Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L (April 1998). "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. doi:10.1093/hmg/7.4.679. PMID 9499421.
• Bérubé NG, Mangelsdorf M, Jagla M, Vanderluit J, Garrick D, Gibbons RJ, Higgs DR, Slack RS, Picketts DJ (February 2005). "The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis". The Journal of Clinical Investigation. 115 (2): 258–67. doi:10.1172/JCI22329. PMC 544602. 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.