ATRX

ATRX
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	2JM1, 2LBM, 2LD1, 3QL9, 3QLA, 3QLC, 3QLN, 4W5A
識別子
記号	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
外部ID	OMIM: 300032 MGI: 103067 HomoloGene: 416 GeneCards: ATRX
遺伝子の位置 (ヒト)
染色体	X染色体
終点	77,786,233 bp
遺伝子の位置 (マウス)
染色体	X染色体 (マウス)
終点	104,973,009 bp
遺伝子オントロジー
分子機能	• DNA結合; • ヌクレオチド結合; • chromo shadow domain binding; • helicase activity; • histone binding; • 金属イオン結合; • DNA translocase activity; • methylated histone binding; • DNA helicase activity; • 血漿タンパク結合; • 加水分解酵素活性; • ATP binding; • クロマチン結合; • DNA-binding transcription factor activity, RNA polymerase II-specific;
細胞の構成要素	• PML body; • SWI/SNF superfamily-type complex; • pericentric heterochromatin; • 染色体; • ヘテロクロマチン; • nuclear chromosome; • テロメア; • 細胞核; • 核質; • 核内構造体;
生物学的プロセス	• クロマチンリモデリング; • 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メチル化; • negative regulation of telomeric RNA transcription from RNA pol II promoter; • seminiferous tubule development; • 精子形成; • replication fork processing; • negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric; • 前脳発生; • DNA修復; • cellular response to hydroxyurea; • positive regulation of transcription by RNA polymerase II; • DNA duplex unwinding; • regulation of histone H3-K9 trimethylation; • meiotic spindle organization; • chromosome organization involved in meiotic cell cycle; • chromatin organization;
	出典:Amigo / QuickGO
オルソログ
	546
	22589
	ENSG00000085224
	ENSMUSG00000031229
	P46100
	Q61687
	NM_000489; NM_138270; NM_138271
	NM_009530
	NP_000480; NP_612114
	NP_033556
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

ATRX（alpha thalassemia/mental retardation syndrome X-linked）は、ヒトではATRX遺伝子にコードされるタンパク質である^[5]^[6]^[7]。

機能

転写調節因子ATRXはATPアーゼ/ヘリカーゼドメインを持つ、SWI/SNFファミリーのクロマチンリモデリング因子である。ATRXはテロメアやその他ゲノム上の反復領域へのヒストンバリアントH3.3の蓄積に必要である^[8]。その作用は、こうした部位でのサイレンシングの維持に重要である^[9]^[10]^[11]。

ATRXは細胞周期依存的なリン酸化を受け、核マトリックス（英語版）やクロマチンへの結合が調節されている。このことは、ATRXが間期における遺伝子調節や有糸分裂時の染色体分離に関与していることを示唆している^[7]。

臨床的意義

遺伝性変異

ATRX遺伝子の遺伝性変異は、ATR-X症候群と関係している。こうした変異はDNAメチル化パターンに多様な変化を引き起こすことから、ATRXは発生過程におけるクロマチンリモデリング、DNAメチル化、そして遺伝子発現を関連付けている可能性がある。女性の変異保因者では偏った（skewed）X染色体不活性化がみられる^[7]。

体細胞変異

ATRXの後天的変異は、膵神経内分泌腫瘍（英語版）^[12]、神経膠腫^[13]^[14]、骨肉腫^[15]、悪性褐色細胞腫^[16]など、いくつかのがんで報告されている。がんでは、ATRXの変異とテロメラーゼ非依存的なテロメア伸長（alternative lengthening of telomere、ALT）との強い相関がみられる^[12]。

相互作用

ATRXは、H3.3に対するシャペロン（ヒストンシャペロン）であるDAXX（英語版）と複合体を形成する^[17]。

ATRXはEZH2と相互作用することも示されている^[18]。

出典

^ ^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:
^ Mouse PubMed Reference:
^ Stayton, C. L.; Dabovic, B.; Gulisano, M.; Gecz, J.; Broccoli, V.; Giovanazzi, S.; Bossolasco, M.; Monaco, L. et al. (1994-11). “Cloning and characterization of a new human Xq13 gene, encoding a putative helicase”. Human Molecular Genetics 3 (11): 1957–1964. doi:10.1093/hmg/3.11.1957. ISSN 0964-6906. PMID 7874112.
^ Gibbons, R. J.; Suthers, G. K.; Wilkie, A. O.; Buckle, V. J.; Higgs, D. R. (1992-11). “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): 1136–1149. ISSN 0002-9297. PMC 1682840. PMID 1415255.
^ ^a ^b ^c “ATRX ATRX chromatin remodeler [Homo sapiens (human) - Gene - NCBI]” (英語). www.ncbi.nlm.nih.gov. 2023年5月6日閲覧。
^ Wong, Lee H.; McGhie, James D.; Sim, Marcus; Anderson, Melissa A.; Ahn, Soyeon; Hannan, Ross D.; George, Amee J.; Morgan, Kylie A. et al. (2010-03). “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 1549-5469. PMC 2840985. PMID 20110566.
^ Voon, Hsiao P. J.; Hughes, Jim R.; Rode, Christina; De La Rosa-Velázquez, Inti A.; Jenuwein, Thomas; Feil, Robert; Higgs, Douglas R.; Gibbons, Richard J. (2015-04-21). “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. ISSN 2211-1247. PMC 4410944. PMID 25865896.
^ Elsässer, Simon J.; Noh, Kyung-Min; Diaz, Nichole; Allis, C. David; Banaszynski, Laura A. (2015-06-11). “Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells”. Nature 522 (7555): 240–244. doi:10.1038/nature14345. ISSN 1476-4687. PMC 4509593. PMID 25938714.
^ Udugama, Maheshi; M Chang, Fiona T.; Chan, F. Lyn; Tang, Michelle C.; Pickett, Hilda A.; R McGhie, James D.; Mayne, Lynne; Collas, Philippe et al. (2015-12-02). “Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres”. Nucleic Acids Research 43 (21): 10227–10237. doi:10.1093/nar/gkv847. ISSN 1362-4962. PMC 4666390. PMID 26304540.
^ ^a ^b Heaphy, Christopher M.; de Wilde, Roeland F.; Jiao, Yuchen; Klein, Alison P.; Edil, Barish H.; Shi, Chanjuan; Bettegowda, Chetan; Rodriguez, Fausto J. et al. (2011-07-22). “Altered telomeres in tumors with ATRX and DAXX mutations”. Science (New York, N.Y.) 333 (6041): 425. doi:10.1126/science.1207313. ISSN 1095-9203. PMC 3174141. PMID 21719641.
^ Schwartzentruber, Jeremy; Korshunov, Andrey; Liu, Xiao-Yang; Jones, David T. W.; Pfaff, Elke; Jacob, Karine; Sturm, Dominik; Fontebasso, Adam M. et al. (2012-01-29). “Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma”. Nature 482 (7384): 226–231. doi:10.1038/nature10833. ISSN 1476-4687. PMID 22286061.
^ Kannan, Kasthuri; Inagaki, Akiko; Silber, Joachim; Gorovets, Daniel; Zhang, Jianan; Kastenhuber, Edward R.; Heguy, Adriana; Petrini, John H. et al. (2012-10). “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 et al. (2014-04-10). “Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma”. Cell Reports 7 (1): 104–112. doi:10.1016/j.celrep.2014.03.003. ISSN 2211-1247. PMC 4096827. PMID 24703847.
^ Comino-Méndez, Iñaki; Tejera, Águeda M.; Currás-Freixes, María; Remacha, Laura; Gonzalvo, Pablo; Tonda, Raúl; Letón, Rocío; Blasco, María A. et al. (2016-06). “ATRX driver mutation in a composite malignant pheochromocytoma”. Cancer Genetics 209 (6): 272–277. doi:10.1016/j.cancergen.2016.04.058. ISSN 2210-7762. PMID 27209355.
^ 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 of the United States of America 107 (32): 14075–14080. doi:10.1073/pnas.1008850107. ISSN 1091-6490. PMC 2922592. PMID 20651253.
^ Cardoso, C.; Timsit, S.; Villard, L.; Khrestchatisky, M.; Fontès, M.; Colleaux, L. (1998-04). “Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein”. Human Molecular Genetics 7 (4): 679–684. doi:10.1093/hmg/7.4.679. ISSN 0964-6906. PMID 9499421.

外部リンク

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.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000085224 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000031229 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[5] Stayton, C. L.; Dabovic, B.; Gulisano, M.; Gecz, J.; Broccoli, V.; Giovanazzi, S.; Bossolasco, M.; Monaco, L. et al. (1994-11). “Cloning and characterization of a new human Xq13 gene, encoding a putative helicase”. Human Molecular Genetics 3 (11): 1957–1964. doi:10.1093/hmg/3.11.1957. ISSN 0964-6906. PMID 7874112.

[6] Gibbons, R. J.; Suthers, G. K.; Wilkie, A. O.; Buckle, V. J.; Higgs, D. R. (1992-11). “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): 1136–1149. ISSN 0002-9297. PMC 1682840. PMID 1415255.

[:0-7] “ATRX ATRX chromatin remodeler [Homo sapiens (human) - Gene - NCBI]” (英語). www.ncbi.nlm.nih.gov. 2023年5月6日閲覧。

[8] Wong, Lee H.; McGhie, James D.; Sim, Marcus; Anderson, Melissa A.; Ahn, Soyeon; Hannan, Ross D.; George, Amee J.; Morgan, Kylie A. et al. (2010-03). “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 1549-5469. PMC 2840985. PMID 20110566.

[9] Voon, Hsiao P. J.; Hughes, Jim R.; Rode, Christina; De La Rosa-Velázquez, Inti A.; Jenuwein, Thomas; Feil, Robert; Higgs, Douglas R.; Gibbons, Richard J. (2015-04-21). “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. ISSN 2211-1247. PMC 4410944. PMID 25865896.

[10] Elsässer, Simon J.; Noh, Kyung-Min; Diaz, Nichole; Allis, C. David; Banaszynski, Laura A. (2015-06-11). “Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells”. Nature 522 (7555): 240–244. doi:10.1038/nature14345. ISSN 1476-4687. PMC 4509593. PMID 25938714.

[11] Udugama, Maheshi; M Chang, Fiona T.; Chan, F. Lyn; Tang, Michelle C.; Pickett, Hilda A.; R McGhie, James D.; Mayne, Lynne; Collas, Philippe et al. (2015-12-02). “Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres”. Nucleic Acids Research 43 (21): 10227–10237. doi:10.1093/nar/gkv847. ISSN 1362-4962. PMC 4666390. PMID 26304540.

[:1-12] Heaphy, Christopher M.; de Wilde, Roeland F.; Jiao, Yuchen; Klein, Alison P.; Edil, Barish H.; Shi, Chanjuan; Bettegowda, Chetan; Rodriguez, Fausto J. et al. (2011-07-22). “Altered telomeres in tumors with ATRX and DAXX mutations”. Science (New York, N.Y.) 333 (6041): 425. doi:10.1126/science.1207313. ISSN 1095-9203. PMC 3174141. PMID 21719641.

[13] Schwartzentruber, Jeremy; Korshunov, Andrey; Liu, Xiao-Yang; Jones, David T. W.; Pfaff, Elke; Jacob, Karine; Sturm, Dominik; Fontebasso, Adam M. et al. (2012-01-29). “Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma”. Nature 482 (7384): 226–231. doi:10.1038/nature10833. ISSN 1476-4687. PMID 22286061.

[14] Kannan, Kasthuri; Inagaki, Akiko; Silber, Joachim; Gorovets, Daniel; Zhang, Jianan; Kastenhuber, Edward R.; Heguy, Adriana; Petrini, John H. et al. (2012-10). “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.

[15] Chen, Xiang; Bahrami, Armita; Pappo, Alberto; Easton, John; Dalton, James; Hedlund, Erin; Ellison, David; Shurtleff, Sheila et al. (2014-04-10). “Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma”. Cell Reports 7 (1): 104–112. doi:10.1016/j.celrep.2014.03.003. ISSN 2211-1247. PMC 4096827. PMID 24703847.

[16] Comino-Méndez, Iñaki; Tejera, Águeda M.; Currás-Freixes, María; Remacha, Laura; Gonzalvo, Pablo; Tonda, Raúl; Letón, Rocío; Blasco, María A. et al. (2016-06). “ATRX driver mutation in a composite malignant pheochromocytoma”. Cancer Genetics 209 (6): 272–277. doi:10.1016/j.cancergen.2016.04.058. ISSN 2210-7762. PMID 27209355.

[17] 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 of the United States of America 107 (32): 14075–14080. doi:10.1073/pnas.1008850107. ISSN 1091-6490. PMC 2922592. PMID 20651253.

[18] Cardoso, C.; Timsit, S.; Villard, L.; Khrestchatisky, M.; Fontès, M.; Colleaux, L. (1998-04). “Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein”. Human Molecular Genetics 7 (4): 679–684. doi:10.1093/hmg/7.4.679. ISSN 0964-6906. PMID 9499421.

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