ATRX: Difference between revisions
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→External links: Adding link to RAD54L gene details page and display in UCSC genome browser. |
Updated entry with latest (post 2009) discoveries. Described major new functions of ATRX in depositing H3.3 and maintaining silencing at telomeres. Added discoveries of ATRX mutations in cancers. |
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== Function == |
== Function == |
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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 [[Histone H3|H3.3]] at [[Telomere|telomeres]] and other genomic repeats <ref>{{Cite journal|last=Wong|first=Lee H.|last2=McGhie|first2=James D.|last3=Sim|first3=Marcus|last4=Anderson|first4=Melissa A.|last5=Ahn|first5=Soyeon|last6=Hannan|first6=Ross D.|last7=George|first7=Amee J.|last8=Morgan|first8=Kylie A.|last9=Mann|first9=Jeffrey R.|date=2017-01-15|title=ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840985/|journal=Genome Research|volume=20|issue=3|pages=351–360|doi=10.1101/gr.101477.109|issn=1088-9051|pmc=2840985|pmid=20110566}}</ref>. These interactions are important for maintaining silencing at these sites <ref>{{Cite journal|last=Voon|first=Hsiao P.J.|last2=Hughes|first2=Jim R.|last3=Rode|first3=Christina|last4=Rosa-Velázquez|first4=Inti A. De La|last5=Jenuwein|first5=Thomas|last6=Feil|first6=Robert|last7=Higgs|first7=Douglas R.|last8=Gibbons|first8=Richard J.|title=ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes|url=http://dx.doi.org/10.1016/j.celrep.2015.03.036|journal=Cell Reports|volume=11|issue=3|pages=405–418|doi=10.1016/j.celrep.2015.03.036|pmc=4410944|pmid=25865896}}</ref><ref>{{Cite journal|last=Elsässer|first=Simon J.|last2=Noh|first2=Kyung-Min|last3=Diaz|first3=Nichole|last4=Allis|first4=C. David|last5=Banaszynski|first5=Laura A.|title=Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells|url=http://www.nature.com/doifinder/10.1038/nature14345|journal=Nature|volume=522|issue=7555|pages=240–244|doi=10.1038/nature14345|pmc=4509593|pmid=25938714}}</ref><ref>{{Cite journal|last=Udugama|first=Maheshi|last2=Chang|first2=Fiona T. M.|last3=Chan|first3=F. Lyn|last4=Tang|first4=Michelle C.|last5=Pickett|first5=Hilda A.|last6=McGhie|first6=James D. R.|last7=Mayne|first7=Lynne|last8=Collas|first8=Philippe|last9=Mann|first9=Jeffrey R.|date=2015-12-02|title=Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres|url=https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkv847|journal=Nucleic Acids Research|volume=43|issue=21|doi=10.1093/nar/gkv847|issn=0305-1048|pmc=4666390|pmid=26304540}}</ref>. |
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== Clinical significance == |
== Clinical significance == |
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=== Inherited mutations === |
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Inherited mutations of the ATRX gene are associated with an X-linked mental retardation ([[X-linked alpha thalassemia mental retardation syndrome|XLMR]]) syndrome most often accompanied by [[alpha-thalassemia mental retardation syndrome|alpha-thalassemia]] ([[Alpha-thalassemia mental retardation syndrome|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]].<ref name="entrez" /> |
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=== Somatic mutations === |
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Acquired mutations in ATRX have been reported in a number of human cancers including pancreatic neuroendocrine tumours<ref name=":0">{{Cite journal|last=Heaphy|first=Christopher M.|last2=Wilde|first2=Roeland F. de|last3=Jiao|first3=Yuchen|last4=Klein|first4=Alison P.|last5=Edil|first5=Barish H.|last6=Shi|first6=Chanjuan|last7=Bettegowda|first7=Chetan|last8=Rodriguez|first8=Fausto J.|last9=Eberhart|first9=Charles G.|date=2011-07-22|title=Altered Telomeres in Tumors with ATRX and DAXX Mutations|url=http://science.sciencemag.org/content/333/6041/425|journal=Science|language=en|volume=333|issue=6041|pages=425–425|doi=10.1126/science.1207313|issn=0036-8075|pmc=3174141|pmid=21719641}}</ref>, gliomas<ref>{{Cite journal|last=Schwartzentruber|first=Jeremy|last2=Korshunov|first2=Andrey|last3=Liu|first3=Xiao-Yang|last4=Jones|first4=David T. W.|last5=Pfaff|first5=Elke|last6=Jacob|first6=Karine|last7=Sturm|first7=Dominik|last8=Fontebasso|first8=Adam M.|last9=Quang|first9=Dong-Anh Khuong|title=Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma|url=http://www.nature.com/doifinder/10.1038/nature10833|journal=Nature|volume=482|issue=7384|pages=226–231|doi=10.1038/nature10833}}</ref>, astrocytomas<ref>{{Cite journal|last=Kannan|first=Kasthuri|last2=Inagaki|first2=Akiko|last3=Silber|first3=Joachim|last4=Gorovets|first4=Daniel|last5=Zhang|first5=Jianan|last6=Kastenhuber|first6=Edward R.|last7=Heguy|first7=Adriana|last8=Petrini|first8=John H.|last9=Chan|first9=Timothy A.|date=2012-10-11|title=Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma|url=http://oncotarget.com/abstract/689|journal=Oncotarget|volume=3|issue=10|pages=1194–1203|doi=10.18632/oncotarget.689|issn=1949-2553|pmc=3717947|pmid=23104868}}</ref> and osteosarcomas<ref>{{Cite journal|last=Chen|first=Xiang|last2=Bahrami|first2=Armita|last3=Pappo|first3=Alberto|last4=Easton|first4=John|last5=Dalton|first5=James|last6=Hedlund|first6=Erin|last7=Ellison|first7=David|last8=Shurtleff|first8=Sheila|last9=Wu|first9=Gang|title=Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma|url=http://dx.doi.org/10.1016/j.celrep.2014.03.003|journal=Cell Reports|volume=7|issue=1|pages=104–112|doi=10.1016/j.celrep.2014.03.003|pmc=4096827|pmid=24703847}}</ref>. There is a strong correlation between ATRX mutations and an [[Telomere#ALT .28Alternative Lengthening of Telomeres.29 and cancer|Alternative Lengthening of Telomeres (ALT)]] phenotype in cancers<ref name=":0" />. |
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== Interactions == |
== Interactions == |
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ATRX forms a complex with [[DAXX]] which is an histone H3.3 chaperone<ref>{{Cite journal|last=Lewis|first=Peter W.|last2=Elsaesser|first2=Simon J.|last3=Noh|first3=Kyung-Min|last4=Stadler|first4=Sonja C.|last5=Allis|first5=C. David|date=2010-08-10|title=Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres|url=http://www.pnas.org/content/107/32/14075|journal=Proceedings of the National Academy of Sciences|language=en|volume=107|issue=32|pages=14075–14080|doi=10.1073/pnas.1008850107|issn=0027-8424|pmc=2922592|pmid=20651253}}</ref>. |
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| ⚫ | ATRX has been shown to [[Protein-protein interaction|interact]] with [[EZH2]].<ref name="pmid9499421">{{cite journal | vauthors = Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L | title = Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein | journal = Hum. Mol. Genet. | volume = 7 | issue = 4 | pages = 679–84 | year = 1998 | pmid = 9499421 | doi = 10.1093/hmg/7.4.679 }}</ref> |
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| ⚫ | ATRX has been also shown to [[Protein-protein interaction|interact]] with [[EZH2]].<ref name="pmid9499421">{{cite journal | vauthors = Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L | title = Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein | journal = Hum. Mol. Genet. | volume = 7 | issue = 4 | pages = 679–84 | year = 1998 | pmid = 9499421 | doi = 10.1093/hmg/7.4.679 }}</ref> |
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== See also == |
== See also == |
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Revision as of 09:31, 15 January 2017
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]
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] and osteosarcomas[15]. 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[16].
ATRX has been also shown to interact with EZH2.[17]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000085224 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031229 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Stayton CL, Dabovic B, Gulisano M, Gecz J, Broccoli V, Giovanazzi S, Bossolasco M, Monaco L, Rastan S, Boncinelli E (April 1995). "Cloning and characterization of a new human Xq13 gene, encoding a putative helicase". Hum Mol Genet. 3 (11): 1957–64. doi:10.1093/hmg/3.11.1957. PMID 7874112.
- ^ 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". Am J Hum Genet. 51 (5): 1136–49. PMC 1682840. PMID 1415255.
- ^ a b c "Entrez Gene: ATRX alpha thalassemia/mental retardation syndrome X-linked (RAD54 homolog, S. cerevisiae)".
- ^ Wong, Lee H.; McGhie, James D.; Sim, Marcus; Anderson, Melissa A.; Ahn, Soyeon; Hannan, Ross D.; George, Amee J.; Morgan, Kylie A.; Mann, Jeffrey R. (2017-01-15). "ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells". Genome Research. 20 (3): 351–360. doi:10.1101/gr.101477.109. ISSN 1088-9051. PMC 2840985. PMID 20110566.
- ^ Voon, Hsiao P.J.; Hughes, Jim R.; Rode, Christina; Rosa-Velázquez, Inti A. De La; Jenuwein, Thomas; Feil, Robert; Higgs, Douglas R.; Gibbons, Richard J. "ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes". Cell Reports. 11 (3): 405–418. doi:10.1016/j.celrep.2015.03.036. PMC 4410944. PMID 25865896.
- ^ Elsässer, Simon J.; Noh, Kyung-Min; Diaz, Nichole; Allis, C. David; Banaszynski, Laura A. "Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells". Nature. 522 (7555): 240–244. doi:10.1038/nature14345. PMC 4509593. PMID 25938714.
- ^ Udugama, Maheshi; Chang, Fiona T. M.; Chan, F. Lyn; Tang, Michelle C.; Pickett, Hilda A.; McGhie, James D. R.; Mayne, Lynne; Collas, Philippe; Mann, Jeffrey R. (2015-12-02). "Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres". Nucleic Acids Research. 43 (21). doi:10.1093/nar/gkv847. ISSN 0305-1048. PMC 4666390. PMID 26304540.
- ^ a b Heaphy, Christopher M.; Wilde, Roeland F. de; Jiao, Yuchen; Klein, Alison P.; Edil, Barish H.; Shi, Chanjuan; Bettegowda, Chetan; Rodriguez, Fausto J.; Eberhart, Charles G. (2011-07-22). "Altered Telomeres in Tumors with ATRX and DAXX Mutations". Science. 333 (6041): 425–425. doi:10.1126/science.1207313. ISSN 0036-8075. PMC 3174141. PMID 21719641.
- ^ Schwartzentruber, Jeremy; Korshunov, Andrey; Liu, Xiao-Yang; Jones, David T. W.; Pfaff, Elke; Jacob, Karine; Sturm, Dominik; Fontebasso, Adam M.; Quang, Dong-Anh Khuong. "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma". Nature. 482 (7384): 226–231. doi:10.1038/nature10833.
- ^ Kannan, Kasthuri; Inagaki, Akiko; Silber, Joachim; Gorovets, Daniel; Zhang, Jianan; Kastenhuber, Edward R.; Heguy, Adriana; Petrini, John H.; Chan, Timothy A. (2012-10-11). "Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma". Oncotarget. 3 (10): 1194–1203. doi:10.18632/oncotarget.689. ISSN 1949-2553. PMC 3717947. PMID 23104868.
- ^ Chen, Xiang; Bahrami, Armita; Pappo, Alberto; Easton, John; Dalton, James; Hedlund, Erin; Ellison, David; Shurtleff, Sheila; Wu, Gang. "Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma". Cell Reports. 7 (1): 104–112. doi:10.1016/j.celrep.2014.03.003. PMC 4096827. PMID 24703847.
- ^ Lewis, Peter W.; Elsaesser, Simon J.; Noh, Kyung-Min; Stadler, Sonja C.; Allis, C. David (2010-08-10). "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. 107 (32): 14075–14080. doi:10.1073/pnas.1008850107. ISSN 0027-8424. PMC 2922592. PMID 20651253.
- ^ Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L (1998). "Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein". Hum. Mol. Genet. 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". Am. J. Med. Genet. 43 (1–2): 383–91. doi:10.1002/ajmg.1320430159. PMID 1605216.
- Tang P, Park DJ, Marshall Graves JA, Harley VR (2005). "ATRX and sex differentiation". Trends Endocrinol. Metab. 15 (7): 339–44. doi:10.1016/j.tem.2004.07.006. PMID 15350606.
- Forget BG (2006). "De novo and acquired forms of alpha thalassemia". Curr. Hematol. Rep. 5 (1): 11–4. PMID 16537041.
- Adès LC, Kerr B, Turner G, Wise G (1992). "Smith-Fineman-Myers syndrome in two brothers". Am. J. Med. Genet. 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)". Am. J. Med. Genet. 30 (1–2): 493–508. doi:10.1002/ajmg.1320300152. PMID 3177467.
- Shapiro MB, Senapathy P (1987). "RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression". Nucleic Acids Res. 15 (17): 7155–74. doi:10.1093/nar/15.17.7155. PMC 306199. PMID 3658675.
- Gibbons RJ, Picketts DJ, Villard L, Higgs DR (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 (1995). "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 (1994). "Cloning and expression of the murine homologue of a putative human X-linked nuclear protein gene closely linked to PGK1 in Xq13.3". Hum. Mol. Genet. 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 (1996). "XNP mutation in a large family with Juberg-Marsidi syndrome". Nat. Genet. 12 (4): 359–60. doi:10.1038/ng0496-359. PMID 8630485.
- Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 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 (1997). "ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome". Hum. Mol. Genet. 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". Eur. J. Hum. Genet. 4 (6): 316–20. PMID 9043863.
- Villard L, Lossi AM, Cardoso C, Proud V, Chiaroni P, Colleaux L, Schwartz C, Fontés M (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 (1997). "Interaction of human recombination proteins Rad51 and Rad54". Nucleic Acids Res. 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 (1997). "Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain". Nat. Genet. 17 (2): 146–8. doi:10.1038/ng1097-146. PMID 9326931.
- Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L (1998). "Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein". Hum. Mol. Genet. 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 (2005). "The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis". J. Clin. Invest. 115 (2): 258–267. 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.
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