Wikipedia

ATM (gen)

ATM serin/treonin-kinaza, simbol ATM, je serin/treonineska protein-kinaza koja se regrutira i aktivira dvolančane prekide DNK. Fosforilizira nekoliko ključnih proteina koji iniciraju aktivaciju kontrolne tačke oštećenja DNK, što dovodi do zaustavljanja ćelijskog ciklusa, poravnavanja DNK ili apoptoza. Nekoliko ovih meta, uključujući p53, CHK2, BRCA1, NBS1 i H2AX su supresori tumora.

ATM (gen)
Identifikatori
AliasiATM
Vanjski ID-jeviOMIM: 607585 MGI: 107202 HomoloGene: 30952 GeneCards: ATM
Lokacija gena (čovjek)
Hromosom 11 (čovjek)
Hrom.Hromosom 11 (čovjek)[1]
Hromosom 11 (čovjek)
Genomska lokacija za ATM (gen)
Genomska lokacija za ATM (gen)
Bend11q22.3Početak108,223,044 bp[1]
Kraj108,369,102 bp[1]
Lokacija gena (miš)
Hromosom 9 (miš)
Hrom.Hromosom 9 (miš)[2]
Hromosom 9 (miš)
Genomska lokacija za ATM (gen)
Genomska lokacija za ATM (gen)
Bend9 A5.3|9 29.12 cMPočetak53,350,449 bp[2]
Kraj53,448,040 bp[2]
Ontologija gena
Molekularna funkcija• aktivnost sa transferazom
• vezivanje sa DNK
• nucleotide binding
• protein kinase activity
• DNA-dependent protein kinase activity
• protein dimerization activity
• protein N-terminus binding
• 1-phosphatidylinositol-3-kinase activity
• kinase activity
• protein serine/threonine kinase activity
• GO:0001948, GO:0016582 vezivanje za proteine
• ATP binding
• GO:0032403 protein-containing complex binding
Ćelijska komponenta• citoplazma
• DNA repair complex
• Diobeno vreteno
• nukleoplazma
• Telomera
• GO:0016023 citoplazmatska vezikula
• jedro
• Jedarce
Biološki proces• somitogenesis
• response to ionizing radiation
• neuron apoptotic process
• reciprocal meiotic recombination
• DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
• response to hypoxia
• female gamete generation
• determination of adult lifespan
• Fosforilacija
• establishment of protein-containing complex localization to telomere
• meiotic telomere clustering
• peptidyl-serine autophosphorylation
• DNA damage checkpoint signaling
• regulation of telomerase activity
• positive regulation of telomerase catalytic core complex assembly
• positive regulation of telomere maintenance via telomerase
• positive regulation of neuron death
• mitotic spindle assembly checkpoint signaling
• oocyte development
• lipoprotein catabolic process
• regulation of cell cycle
• protein phosphorylation
• heart development
• brain development
• positive regulation of neuron apoptotic process
• negative regulation of telomere capping
• positive regulation of telomere maintenance via telomere lengthening
• GO:0035404 peptidyl-serine phosphorylation
• cellular response to gamma radiation
• intrinsic apoptotic signaling pathway in response to DNA damage
• V(D)J rekombinacija
• positive regulation of apoptotic process
• regulation of cellular response to heat
• pre-B cell allelic exclusion
• ćelijski ciklus
• histone mRNA catabolic process
• cellular response to nitrosative stress
• positive regulation of DNA damage response, signal transduction by p53 class mediator
• double-strand break repair via nonhomologous end joining
• negative regulation of B cell proliferation
• GO:0072468 Transdukcija signala
• establishment of RNA localization to telomere
• GO:0097285 apoptoza
• Replikacija DNK
• DNA double-strand break processing
• regulation of signal transduction by p53 class mediator
• regulation of autophagy
• phosphatidylinositol-3-phosphate biosynthetic process
• cellular response to X-ray
• double-strand break repair via homologous recombination
• regulation of apoptotic process
• negative regulation of TORC1 signaling
• ovarian follicle development
• immune system process
• immunoglobulin production
• DNA damage induced protein phosphorylation
• male meiotic nuclear division
• female meiotic nuclear division
• female gonad development
• post-embryonic development
• multicellular organism growth
• protein autophosphorylation
• thymus development
• GO:0051178 chromosome organization involved in meiotic cell cycle
• GO:0100026 Popravka DNK
• cellular response to DNA damage stimulus
• regulation of telomere maintenance via telomerase
• positive regulation of DNA catabolic process
• regulation of microglial cell activation
• regulation of cellular response to gamma radiation
• positive regulation of response to DNA damage stimulus
• telomere maintenance
• replicative senescence
• GO:1901313 positive regulation of gene expression
• positive regulation of cell migration
• positive regulation of cell adhesion
• GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
• cellular response to retinoic acid
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

472

11920

Ensembl

ENSG00000149311

ENSMUSG00000034218

UniProt

Q13315

Q62388

RefSeq (mRNK)
NM_000051
NM_138292
NM_138293
NM_001351834
NM_001351835

NM_001351836

NM_007499

RefSeq (bjelančevina)

NP_000042
NP_001338763
NP_001338764
NP_001338765
NP_000042.3

NP_031525

Lokacija (UCSC)Chr 11: 108.22 – 108.37 MbChr 9: 53.35 – 53.45 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Godine 1995., gen je otkrio dr Yosef Shiloh[5] koji je svoj proizvod nazvao ATM jer je otkrio da su njegove mutacije odgovorne za poremećaj ataksija – telangiektazija.[6] U 1998, laboratorije Shiloh i Kastan nezavisno su pokazale da je ATM protein-kinaza, čija je aktivnost pojačana oštećenjem DNK.[7][8]

Četiri poznata konzervirna domena u četiri člana porodice PIKK

Funkcija

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Kompleks od tri proteina: MRE11, RAD50 i NBS1 (XRS2 u kvascu), zvani MRN složen kod ljudi, regrutuje ATM na dvolančane prekide (DSB) i drži dva kraja zajedno. ATM direktno stupa u interakciju sa podjedinicom NBS1 i fosforilizira histonsku varijantu H2AX na Ser139.[9] Ova fosforilacija generira mjesta vezanja za adapterske proteine sa BRCT-domenom. Ovi adapterski proteini tada regrutiraju različite faktore uključujući efektorsku protein kinazu CHK2 i supresor tumora p53. Odgovor na oštećenje DNK posredstvom ATM-a sastoji se od brzog i odgođenog odgovora. Efektorna kinaza CHK2 je fosforilirana i aktivirana pomoću ATM-a. Aktivirani CHK2 fosforilira fosfatazu CDC25A, koja se zatim razgrađuje i više ne može defosforilirati CDK1-ciklin-B, što rezultira zaustavljanjem ćelijskog ciklusa. Ako se DSB ne može popraviti tokom ovog brzog odgovora, ATM dodatno fosforilira MDM2 i p53 na Ser15.[10] I p53 je također fosforiliran efektorskom kinazom CHK2. Ovi događaji fosforilacija dovode do stabilizacije i aktivacije p53 i kasnije transkripcije brojnih gena za ciljanje p53, uključujući inhibitor CDK p21 što dovodi do dugotrajnog zastoja u ćelijskom ciklusu ili čak do apoptoze.[11]

 
ATM-posredovani dvostepeni odgovor na prekide dvostrukih lanaca DNK. U brzom odgovoru, aktivirani ATM fosforilira efektorski kinazu CHK2 koja fosforilira CDC25A, ciljajući je na ubikvitinaciju i razgradnju.
Zato se fosforilirani CDK2-ciklin akumulira i progresija kroz ćelijski ciklus je blokirana. U odgođenom odgovoru, ATM fosforilizira inhibitore p53, MDM2 i p53, koji je takođe fosforilizirao Chk2. Rezultirajuća aktivacija i stabilizacija p53 dovodi do povećane ekspresije inhibitora Cdk p21, što dodatno pomaže u održavanju niske aktivnosti Cdk i u održavanju dugotrajnog zastoja ćelijskog ciklusa.[11]

ATM protein-kinaze također može biti uključen u mitohondrijsku homeostazu, kao regulator mitohondrijske autofagije] (mitofagije) pri čemu se uklanjaju stare, disfunkcionalne mitohondrije.[12] Povećana aktivnost ATM-a javlja se i kod virusne infekcije gdje se ATM aktivira rano tokom infekcije virusom denga, kao dio indukcije autofagije i odgovora na ER- stres.[13]

Regulacija

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Za aktiviranje ATM nakon DSB-a potreban je funkcionalan kompleks MRN. Kompleks funkcionira uzvodno od ATM-a u ćelijama sisara i izaziva konformacijske promjene koje olakšavaju povećanje afiniteta ATM-a prema njegovim podlogama, poput CHK2 i p53.<ef narme= "pmid18066086"/> Neaktivni ATM prisutan je u ćelijama bez DSB-a u obliku dimera ili multimera. Nakon oštećenja DNK, on se autofosforilira na ostatku Ser1981. Ova fosforilacija izaziva disocijaciju ATM dimera, nakon čega slijedi oslobađanje aktivnih ATM monomera.[14] Dalja autofosforilacija (ostataka Ser367 i Ser1893) potrebna je za normalnu aktivnost ATM-kinaze. Aktivaciji ATM-a kompleksom MRN prethode najmanje dva koraka, tj. regrutiranje ATM-a u DSB završava posrednik proteina 1 kontrolne tačke oštećenja DNK (MDC1) koji se veže do MRE11 i naknadna stimulacija aktivnosti kinaze sa NBS1 C-terminala. Tri domena FAT, PRD i FATC uključena su u regulisanje aktivnosti domena KD-kinaze. FAT domen stupa u interakciju s KD domenom ATM-a, kako bi stabilizirao područje C-kraja samog ATM-a. FATC domen je kritičan za aktivnost kinaze i vrlo je osjetljiv na mutagenezu. Posreduje u interakciji protein-protein, n primjer sa histonskom acetiltransferazom TIP60 (HIV-1 Tat interakcijski protein od 60 kDa), koji acetilira ATM na ostatku Lys3016. Acetilacija se događa u C-terminalnoj polovini PRD-domena i potrebna je za aktivaciju ATM-kinaze i za njenu pretvorbu u monomere. Dok delecija cijelog domena PRD ukida kinaznu aktivnost ATM-a, specifične male delecije ne pokazuju učinak.[15]

Mutacije germinativnih linija i rizik od raka

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Ljudi koji nose heterozigotnu ATM-mutaciju imaju povećan rizik od raka gušterače, prostate, želuca i ivazivnog duktusnog karcinoma dojke.[16] Homozigotna mutacija ATM-a izaziva bolest ataksija – telangiektazija (AT), rijetku ljudsku bolest koju karakterizira cerebelarna degeneracija, ekstremna ćelijskA osjetljivost na zračenje i predispozicija za kancer. Svi AT pacijenti sadrže mutacije u ATM genu. Većina drugih AT-sličnih poremećaja ima defekt u genima koji kodiraju kompleks proteina MRN. Jedna značajka proteina ATM je njegovo brzo povećanje aktivnosti kinaze neposredno nakon formiranja dvostrukog prekida.[17][18] Fenotipska manifestacija posljedica AT je širokog raspona supstrata za ATM-kinazu, uključujući popravak DNK, apoptoza, G1/S, intra-S kontrolnu tačku i G2/M kontrolne tačke, regulacija gena, inicijaciju translacije i održavanje telomera.[19] Stoga, kvar u ATM ima ozbiljne posljedice pri popravljanju određenih tipova oštećenja DNK, a kancer može nastati zbog nepravilnog popravljanja. AT pacijentice imaju povećan rizik od raka dojke koji se pripisuje interakciji ATM-a i fosforilaciji BRCA1 i njegovih povezanih proteina, nakon oštećenja DNK.[20]

Somatske ATM mutacije sporadičnih karcinoma

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Kod sporadičnih karcinoma, mutacije u ATM genu nalaze se na relativno niskim frekvencijama. Prema COSMIC-u, Katalogu somatskih kancerogenih mutacija, učestalosti s kojima se javljaju heterozigotne mutacije u ATM-u kod uobičajenih karcinoma uključuju 0,7% kod 713 karcinoma jajnika, 0,9% kod karcinoma centralnog nervnog sistema, 1,9 % kod 1.120 dojke, 2.1% kod 847 bubrega, 4,6% kod debelog crijeva, 7.2% među 1.040 pluća i 11.1% kod 1790 karcinoma hematopoeze i limfoidnog tkiva.[21] Određene vrste leukemija i limfoma, kao što su limfom plaštanih ćelija, T-ALL, atipska hronična limfocitna leukemija B ćelija i T-PLL su takođeR povezane sa defektim ATP-a.[22] Sveobuhvatna pretraga literature o nedostatku ATM-a u karcinomu gušterače, koja je obuhvatila 5.234 pacijenta, procijenila je da je ukupna prevalencija mutacija zametnih linija ili somatskih ATM mutacija u raku gušterače 6,4%. [23] Mutacije ATM-a mogu poslužiti kao prediktivni biomarkeri odgovora na određene terapije, budući da su pretklinička istraživanja otkrila da nedostatak ATM-a može osjetiti neke tipove raka na inhibiciju ATR inhibicije.[24][25][26][27]

Česti epigenetički nedostaci ATM kod karcinoma

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ATM je jedan od gena za popravak DNK, koji je često hipermetiliran u promotorskoj regiji kod različitih karcinoma. Metilacija promotora ATM -a uzrokuje smanjenu ekspresiju proteina ili iRNK ekspresijew ATM-a.

Utvrđeno je da je više od 73% tumora mozga metilirano u promotoru ATM gena, a postojala je snažna inverzna korelacija između metilacije promotora ATM i njegove ekspresije proteina (p <0,001).[28]

Uočeno je da je promotor ATM gena hipermetiliran u 53% malih (neopipljivih) karcinoma dojke[29] i bio je hipermetiliran u 78% karcinoma dojke II ili stadija s visoko značajnom korelacijom (p = 0,0006) između smanjene količine ATM-ove iRNK i aberantne metilacije promotora ATM gena.[30]

Kod raka pluća nemalih ćelija (NSCLC), stanje metilacije promotora ATM-a uparenih tumora i okolnog histološki nepogođenog plućnog tkiva bilo je 69%, odnosno 59%. Međutim, u naprednijem NSCLC-u učestalost metilacije promotora ATM bila je niža na 22%.[31] Nalaz metilacije promotora ATM-a u okolnom histološki nepogođenom plućnom tkivu sugerira da nedostatak ATM -a može biti prisutan u ranoj fazi defekata polja što dovodi do progresije u NSCLC.

Kod karcinoma pločastih ćelija glave i vrata, 42% tumora pokazalo je metilaciju promotora ATM.[32]

Oštećenje DNK javlja se kao primarni uzrok raka,[33] a nedostaci u popravljanju DNK vjerovatno su u osnovi mnogih oblika raka.[34] Ako je popravak DNK nedostatan, oštećenje DNK se nakuplja. Takva prevelika oštećenja DNK mogu povećati mutacijske greške tokom replikacije DNK zbog sklonosti greškama sinteze translezije. Višak oštećenja DNK također može povećati epigenetičke promjene zbog grešaka tokom popravka DNK.[35][36] Takve mutacije i epigenetičke promjene mogu uzrokovati rak. Česti epigeneički nedostatak ATM-a u brojnim tipovima karcinoma vjerojatno je pridonio nihovojprogresiji.

Mejoza

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Funkcije ATM-a tokom mejotske profaze[37] ATM gena divljeg tipa je eksprimirju se u četiri puta povećanom nivou u ljudskim sjemenicima, u poređenju sa somatskim ćelijama (kao što su kožni fibroblasti).[38] I kod miševa i kod ljudi, nedostatak ATM-a dovodi do ženskr i muške neplodnosti. Nedostatak ekspresije ATM uzrokuje ozbiljne mejotske poremećaje tokom profaze I.[39] Osim toga, oslabljena reparacija DNK DSB posredovana ATM-om identificirana je kao vjerovatni uzrok starenja jajnih ćelija miša i ljudi.[40] Ekspresija gena ATM, kao i drugih ključnih gena za popravak DSB-a, opada s godinama u oocitima miša i ljudi, a to smanjenje je usporedo s povećanjem DSB-a u primordijalnim folikulama.[40] Ovi nalazi ukazuju da ATM- posredovana homologna rekombinacijske popravka ključnafunkcija mejoze.

Interakcije

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Pokazalo se da mutirana ataksija telangiektazija ima interakciju sa:

Tefu

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The Tefu protein of Drosophila melanogaster is a structural and functional homolog of the human ATM protein.[65] Tefu, like ATM, is required for DNA repair and normal levels of meiotic recombination in oocytes.

Također pogledajte

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Reference

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