H2AX

H2AX
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2D31, 2DYP, 3SHV, 3SQD, 3SZM, 1YDP, 2AZM, 3U3Z
Identifikatori
Aliasi	H2AX
Vanjski ID-jevi	OMIM: 601772 MGI: 102688 HomoloGene: 134201 GeneCards: H2AX
Lokacija gena (čovjek)
Hrom.	Hromosom 11 (čovjek)
Kraj	119,095,465 bp
Lokacija gena (miš)
Hrom.	Hromosom 9 (miš)
Kraj	44,247,374 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• vezivanje sa DNK; • GO:0031493 histone binding; • GO:0001948, GO:0016582 vezivanje za proteine; • protein heterodimerization activity; • vezivanje enzima; • oštećeno vezivanje sa DNK;
Ćelijska komponenta	• nukleoplazma; • hromosom; • Telomera; • Nukleosom; • Egzosom; • nuclear speck; • centrosom; • jedro; • site of double-strand break; • Hromatin; • kondenzovani nuklearni hromosom; • male germ cell nucleus; • XY body; • replication fork; • site of DNA damage;
Biološki proces	• response to ionizing radiation; • nucleosome assembly; • DNA recombination; • DNA damage checkpoint signaling; • GO:1900404 positive regulation of DNA repair; • cellular response to DNA damage stimulus; • Ćelijsko starenje; • GO:0007126 Mejoza; • cellular response to gamma radiation; • Spermatogeneza; • cerebral cortex development; • ćelijski ciklus; • GO:0022415 viral process; • double-strand break repair via nonhomologous end joining; • double-strand break repair; • GO:0100026 Popravka DNK; • double-strand break repair via homologous recombination; • GO:0031497, GO:0006336, GO:0034724, GO:0001301, GO:0007580, GO:0034652, GO:0010847 chromatin organization;
	Izvori:Amigo / QuickGO
Ortolozi
	3014
	15270
	ENSG00000188486
	ENSMUSG00000049932
	P16104
	P27661
	NM_002105
	NM_010436
	NP_002096
	NP_034566
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Član X histonske porodice H2A (skr. H2AX) jest histonski protein koji je kod ljudi kodiran genom H2AFX' sa hromosoma 11. Pripada histonskoj porodici H2A; važan fosforilirani oblik mu je γH2AX (S139), koji nastaje kada se pojave dvolančani prekidi.

Kod ljudi i drugih eukariota, DNK je omotana oko histonskih oktamera, koji se sastoje od jezgarnih histona H2A, H2B, H3 i H4, da bi se formirao hromatin. H2AX doprinosi formiranju nukleosoma, remodeliranju hromatina i popravci DNK, a također se koristi in vitro, kao test za dvolančane prekide u dsDNK.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 143 aminokiseline, a molekulska težina 15.145 Da.^[5]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MSGRGKTGGK	ARAKAKSRSS	RAGLQFPVGR	VHRLLRKGHY	AERVGAGAPV
YLAAVLEYLT	AEILELAGNA	ARDNKKTRII	PRHLQLAIRN	DEELNKLLGG
VTIAQGGVLP	NIQAVLLPKK	TSATVGPKAP	SGGKKATQAS	QEY

Formiranje γH2AX

H2AX postaje fosforiliran na serinu 139, koji se tada naziva γH2AX, kao reakcija na dvolančani prekid DNK (DSB). Kinaze iz porodice PI3 (mutirana ataksija telangiektazija, ATR i DNK-PKc) su odgovorne za ovu fosforilaciju, posebno ATM. Modifikacija se može desiti slučajno tokom kolapsa replikacijske viljuške ili kao odgovor na ionizirajuće zračenje, ali i tokom kontrolisanih fizioloških procesa kao što je V(D)J rekombinacija. γH2AX je osjetljiva meta za gledanje DSB-ova u ćelijama. Prisustvo γH2AX samo po sebi, međutim, nije dokaz DSB-ova.^[6] Uloga fosforiliranog oblika histona u popravci DNK je u diskusiji, ali je poznato da zbog modifikacije DNK postaje manje kondenzirana, potencijalno omogućavajući prostor za regrutovanje proteina neophodnih tokom popravke DSB-a. Eksperimenti mutageneze su pokazali da je modifikacija neophodna za pravilno formiranje žarišta izazvanih ionizujućim zračenjem, kao odgovor na prekide dvostrukih lanaca, ali nije potrebna za regrutovanje proteina na mesto DSB.

Funkcija

Reakcija na oštećenje DNK

Histonska varijanta H2AX čini oko 2-25% H2A histona u hromatinu sisara.^[7] Kada dođe do prekida dvostrukog lanca u DNK, dešava se niz događaja u kojima se H2AX mijenja.

Vrlo rano nakon prekida dvostrukog lanca, specifični protein koji stupa u interakciju i utiče na arhitekturu hromatina se fosforilira i zatim oslobađa iz hromatina. Ovaj protein, heterohromatinski protein 1 (HP1)-beta (CBX1), vezan je za histon H3 metiliran na lizinu 9 (H3K9me). Polovično maksimalno oslobađanje HP1-beta iz oštećene DNK događa se unutar jedne sekunde.^[8] Dinamička promjena u strukturi hromatina je pokrenuta oslobađanjem HP1-beta. Ova promjena u strukturi hromatina podstiče fosforilaciju H2AX pomoću ATM, ATR i DNK-PK,^[9] omogućavajući formiranje γH2AX (H2AX fosforiliran na serinu 139). γH2AX se može detektovati već 20 sekundi nakon zračenja ćelija (sa formiranjem dvostrukog lanca DNK), a polovina maksimalne akumulacije γH2AX dešava se u jednoj minuti.^[7] Hromatin sa fosforilisanim γH2AX proteže se do oko milion baznih parova sa svake strane dvolančanog prekida DNK.^[7] MDC1 (posrednik proteinske kontrolne tačke oštećenja DNK 1) se zatim vezuje za γH2AX i kompleks γH2AX/MDC1, a zatim orkestrira dalje interakcije u popravci dvolančanog prekida.^[10] Ubikvitinske ligaze RNF8 i RNF168 vezuju se za kompleks γH2AX/MDC1, ubikvitilirajući druge komponente hromatina. Ovo omogućava regrutaciju BRCA1 i 53BP1 u dugi, modificirani γH2AX/MDC1 hromatin.^[10] Ostali proteini koji se stabilno okupljaju na ekstenzivnom γH2AX-modificiranom hromatinu su MRN kompleks (proteinski kompleks koji se sastoji od Mre11, Rad50 i Nbs1), RAD51 i ATM kinaze.^[11]^[12] Dalje komponente za popravak DNK, kao što su RAD52 i RAD54, brzo i reverzibilno stupaju u interakciju sa komponentama jezgra stabilno povezanim sa γH2AX-modifikovanim hromatinom.^[12] Konstitutivni nivo ekspresije γH2AX u živim ćelijama, netretiranim egzogenim agensima, vjerovatno predstavlja oštećenje DNK endogenim oksidansima nastalim tokom ćelijskog disanja.^[13]

U remodeliranju hromatina

Pakovanje eukariotske DNK u hromatin predstavlja prepreku svim procesima zasnovanim na DNK koji zahtijevaju angažovanje enzima na njihovim mjestima delovanja. Da bi se omogućila popravka DNK, hromatin mora biti remodeliran.

γH2AX, fosforilirani oblik H2AX, uključen je u korake koji vode do dekondenzacije hromatina, nakon prekida dvolančanog DNK. γH2AX sam po sebi ne uzrokuje dekondenzaciju hromatina, ali unutar 30 sekundi od ionizujućeg zračenja, RNF8 protein se može otkriti u vezi sa γH2AX.^[14] RNF8 posreduje u ekstenzivnoj dekondenzaciji hromatina, kroz njegovu naknadnu interakciju sa CHD4,^[15] komponente remodeliranja nukleosoma i kompleksa deacetilaze NuRD.

γH2AX kao test za dvolančane prekide

Test za γH2AX općenito odražava prisustvo dvolančanih prekida u DNK, iako test može ukazati i na druge manje pojave.^[16] S jedne strane, neodoljivi dokazi podržavaju snažnu, kvantitativnu korelaciju između formiranja žarišta γH2AX i indukcije dvostrukog lanca DNK nakon izlaganja ionizujućem zračenju, zasnovanu na apsolutnim prinosima i distribucijama induciranim po jediničnoj dozi.^[16] S druge strane, prijavljeno je ne samo formiranje različitih žarišta γH2AX, već i indukcija panjedarnih γH2AX signala, kao ćelijska reakcija na različite stresore osim ionizujućeg zračenja.^[17] Signal γH2AX je uvijek jači pri prekidima dvolančanih lanaca DNK nego u neoštećenom hromatinu.^[17] Smatra se da je γH2AX u neoštećenom hromatinu moguće generirati direktnimm fosforilacijama H2AX aktiviranim kinazama, najvjerovatnije difundirajući sa mjesta oštećenja DNK. U korištenju γH2AX kao markera za prekide dvostrukih lanaca, važno je prepoznati da je to nizvodni proksi koji može biti koristan za predstavljanje popravke oštećenja DNK. Sami po sebi ne predstavlja dvostruke prekide i to treba pažljivo razmotriti prilikom tumačenja podataka iz takvih testova.^[18]

Interakcije

Pokazalo se da je H2AX u interakciji sa:

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000188486 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000049932 - Ensembl, maj 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.
^ "UniProt, P16104" (jezik: engleski). Arhivirano s originala, 18. 9. 2017. Pristupljeno 25. 1. 2023.
^ Cleaver JE, Feeney L, Revet I (2011). "Phosphorylated H2Ax is not an unambiguous marker for DNA double strand breaks". Cell Cycle. 10 (19): 3223–4. doi:10.4161/cc.10.19.17448. PMID 21921674.
^ ^a ^b ^c Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (1998). "DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139". J. Biol. Chem. 273 (10): 5858–68. doi:10.1074/jbc.273.10.5858. PMID 9488723.
^ Ayoub N, Jeyasekharan AD, Bernal JA, Venkitaraman AR (2008). "HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response". Nature. 453 (7195): 682–6. Bibcode:2008Natur.453..682A. doi:10.1038/nature06875. PMID 18438399. S2CID 4348736.
^ Furuta T, Takemura H, Liao ZY, Aune GJ, Redon C, Sedelnikova OA, Pilch DR, Rogakou EP, Celeste A, Chen HT, Nussenzweig A, Aladjem MI, Bonner WM, Pommier Y (2003). "Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes". J. Biol. Chem. 278 (22): 20303–12. doi:10.1074/jbc.M300198200. PMID 12660252.
^ ^a ^b Scully R, Xie A (2013). "Double strand break repair functions of histone H2AX". Mutat. Res. 750 (1–2): 5–14. doi:10.1016/j.mrfmmm.2013.07.007. PMC 3818383. PMID 23916969.
^ Bekker-Jensen S, Lukas C, Kitagawa R, Melander F, Kastan MB, Bartek J, Lukas J (2006). "Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks". J. Cell Biol. 173 (2): 195–206. doi:10.1083/jcb.200510130. PMC 2063811. PMID 16618811.
^ ^a ^b Essers J, Houtsmuller AB, van Veelen L, Paulusma C, Nigg AL, Pastink A, Vermeulen W, Hoeijmakers JH, Kanaar R (2002). "Nuclear dynamics of RAD52 group homologous recombination proteins in response to DNA damage". EMBO J. 21 (8): 2030–7. doi:10.1093/emboj/21.8.2030. PMC 125370. PMID 11953322.
^ Tanaka T, Halicka HD, Huang X, Traganos F, Darzynkiewicz Z (2006). "Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants". Cell Cycle. 5 (17): 1940–5. doi:10.4161/cc.5.17.3191. PMC 3488278. PMID 16940754.
^ Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J (2007). "RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins". Cell. 131 (5): 887–900. doi:10.1016/j.cell.2007.09.040. PMID 18001824. S2CID 14232192.
^ Luijsterburg MS, Acs K, Ackermann L, Wiegant WW, Bekker-Jensen S, Larsen DH, Khanna KK, van Attikum H, Mailand N, Dantuma NP (2012). "A new non-catalytic role for ubiquitin ligase RNF8 in unfolding higher-order chromatin structure". EMBO J. 31 (11): 2511–27. doi:10.1038/emboj.2012.104. PMC 3365417. PMID 22531782.
^ ^a ^b Rothkamm K, Barnard S, Moquet J, Ellender M, Rana Z, Burdak-Rothkamm S (2015). "DNA damage foci: Meaning and significance". Environ. Mol. Mutagen. 56 (6): 491–504. doi:10.1002/em.21944. PMID 25773265. S2CID 32371215.
^ ^a ^b Meyer B, Voss KO, Tobias F, Jakob B, Durante M, Taucher-Scholz G (2013). "Clustered DNA damage induces pan-nuclear H2AX phosphorylation mediated by ATM and DNA-PK". Nucleic Acids Res. 41 (12): 6109–18. doi:10.1093/nar/gkt304. PMC 3695524. PMID 23620287.
^ Atkinson, Jake; Bezak, Eva; Kempson, Ivan (4. 7. 2022). "Imaging DNA double-strand breaks — are we there yet?". Nature Reviews Molecular Cell Biology. 23 (9): 579–580. doi:10.1038/s41580-022-00513-7. PMID 35789205 Provjerite vrijednost parametra |pmid= (pomoć). S2CID 250283224 Provjerite vrijednost parametra |s2cid= (pomoć).
^ ^a ^b Mallery DL, Vandenberg CJ, Hiom K (Dec 2002). "Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains". The EMBO Journal. 21 (24): 6755–62. doi:10.1093/emboj/cdf691. PMC 139111. PMID 12485996.
^ ^a ^b Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ (Jun 2002). "Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase". The Journal of Biological Chemistry. 277 (24): 22085–92. doi:10.1074/jbc.M201252200. PMID 11927591.
^ Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM (2000). "A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage". Current Biology. 10 (15): 886–95. doi:10.1016/s0960-9822(00)00610-2. PMID 10959836. S2CID 16108315.
^ ^a ^b Sengupta S, Robles AI, Linke SP, Sinogeeva NI, Zhang R, Pedeux R, Ward IM, Celeste A, Nussenzweig A, Chen J, Halazonetis TD, Harris CC (Sep 2004). "Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest". The Journal of Cell Biology. 166 (6): 801–13. doi:10.1083/jcb.200405128. PMC 2172115. PMID 15364958.
^ Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ (Feb 2003). "MDC1 is a mediator of the mammalian DNA damage checkpoint". Nature. 421 (6926): 961–6. Bibcode:2003Natur.421..961S. doi:10.1038/nature01446. PMID 12607005. S2CID 4410773.
^ Xu X, Stern DF (Oct 2003). "NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors". FASEB Journal. 17 (13): 1842–8. doi:10.1096/fj.03-0310com. PMID 14519663. S2CID 24870579.
^ Kobayashi J, Tauchi H, Sakamoto S, Nakamura A, Morishima K, Matsuura S, Kobayashi T, Tamai K, Tanimoto K, Komatsu K (Oct 2002). "NBS1 localizes to γH2AX foci through interaction with the FHA/BRCT domain". Current Biology. 12 (21): 1846–51. doi:10.1016/s0960-9822(02)01259-9. PMID 12419185. S2CID 10686827.
^ Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, Carpenter PB, Bonner WM, Chen J, Nussenzweig A (Dec 2002). "DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1". Nature Cell Biology. 4 (12): 993–7. doi:10.1038/ncb884. PMID 12447390. S2CID 12380387.
^ Ward IM, Minn K, Jorda KG, Chen J (maj 2003). "Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX". The Journal of Biological Chemistry. 278 (22): 19579–82. doi:10.1074/jbc.C300117200. PMID 12697768.

Dopunska literatura

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Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A (2005). "H2AX: the histone guardian of the genome". DNA Repair. 3 (8–9): 959–67. doi:10.1016/j.dnarep.2004.03.024. PMID 15279782.
Mannironi C, Bonner WM, Hatch CL (Nov 1989). "H2A.X. a histone isoprotein with a conserved C-terminal sequence, is encoded by a novel mRNA with both DNA replication type and polyA 3' processing signals". Nucleic Acids Research. 17 (22): 9113–26. doi:10.1093/nar/17.22.9113. PMC 335118. PMID 2587254.
Banerjee S, Smallwood A, Hultén M (Feb 1995). "ATP-dependent reorganization of human sperm nuclear chromatin". Journal of Cell Science. 108 (2): 755–65. doi:10.1242/jcs.108.2.755. PMID 7769017.
Ivanova VS, Hatch CL, Bonner WM (Sep 1994). "Characterization of the human histone H2A.X gene. Comparison of its promoter with other H2A gene promoters". The Journal of Biological Chemistry. 269 (39): 24189–94. doi:10.1016/S0021-9258(19)51067-5. PMID 7929075.
Ivanova VS, Zimonjic D, Popescu N, Bonner WM (Sep 1994). "Chromosomal localization of the human histone H2A.X gene to 11q23.2-q23.3 by fluorescence in situ hybridization". Human Genetics. 94 (3): 303–6. doi:10.1007/BF00208289. PMID 8076949. S2CID 21293682.
Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (Mar 1998). "DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139". The Journal of Biological Chemistry. 273 (10): 5858–68. doi:10.1074/jbc.273.10.5858. PMID 9488723.
El Kharroubi A, Piras G, Zensen R, Martin MA (maj 1998). "Transcriptional activation of the integrated chromatin-associated human immunodeficiency virus type 1 promoter". Molecular and Cellular Biology. 18 (5): 2535–44. doi:10.1128/mcb.18.5.2535. PMC 110633. PMID 9566873.
Rogakou EP, Boon C, Redon C, Bonner WM (Sep 1999). "Megabase chromatin domains involved in DNA double-strand breaks in vivo". The Journal of Cell Biology. 146 (5): 905–16. doi:10.1083/jcb.146.5.905. PMC 2169482. PMID 10477747.
Rogakou EP, Nieves-Neira W, Boon C, Pommier Y, Bonner WM (Mar 2000). "Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139". The Journal of Biological Chemistry. 275 (13): 9390–5. doi:10.1074/jbc.275.13.9390. PMID 10734083.
Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM (2001). "A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage". Current Biology. 10 (15): 886–95. doi:10.1016/S0960-9822(00)00610-2. PMID 10959836. S2CID 16108315.
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Vanjski linkovi

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000188486 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000049932 - Ensembl, maj 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.

[UniProt-5] "UniProt, P16104" (jezik: engleski). Arhivirano s originala, 18. 9. 2017. Pristupljeno 25. 1. 2023.

[6] Cleaver JE, Feeney L, Revet I (2011). "Phosphorylated H2Ax is not an unambiguous marker for DNA double strand breaks". Cell Cycle. 10 (19): 3223–4. doi:10.4161/cc.10.19.17448. PMID 21921674.

[Rogakou_1998-7] Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (1998). "DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139". J. Biol. Chem. 273 (10): 5858–68. doi:10.1074/jbc.273.10.5858. PMID 9488723.

[Ayoub2008-8] Ayoub N, Jeyasekharan AD, Bernal JA, Venkitaraman AR (2008). "HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response". Nature. 453 (7195): 682–6. Bibcode:2008Natur.453..682A. doi:10.1038/nature06875. PMID 18438399. S2CID 4348736.

[pmid12660252-9] Furuta T, Takemura H, Liao ZY, Aune GJ, Redon C, Sedelnikova OA, Pilch DR, Rogakou EP, Celeste A, Chen HT, Nussenzweig A, Aladjem MI, Bonner WM, Pommier Y (2003). "Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes". J. Biol. Chem. 278 (22): 20303–12. doi:10.1074/jbc.M300198200. PMID 12660252.

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