BRCA1

Protein osjetljivosti na rak dojke tip 1 je protein koji je kod ljudi kodiran genom BRCA1.^[5] Ortolozi su česti kod drugih kičmenjačkih vrsta, dok genomi beskičmenjaka mogu imati srodni gen.^[6] BRCA1 je ljudski gen supresije tumora ^[7][8] (poznat i kao domarski gen) i odgovoran je za popravak DNK.^[9]

BRCA1
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 1JM7, 1JNX, 1N5O, 1OQA, 1T15, 1T29, 1T2U, 1T2V, 1Y98, 2ING, 3COJ, 3K0H, 3K0K, 3K15, 3PXA, 3PXB, 3PXC, 3PXD, 3PXE, 4IFI, 4IGK, 4JLU, 4OFB, 4U4A, 4Y18, 4Y2G
Identifikatori
Aliasi	BRCA1
Vanjski ID-jevi	OMIM: 113705 MGI: 104537 HomoloGene: 5276 GeneCards: BRCA1
Lokacija gena (čovjek) Hrom. Hromosom 17 (čovjek)[1] Bend 17q21.31 Početak 43,044,295 bp[1] Kraj 43,170,245 bp[1]
Lokacija gena (miš) Hrom. Hromosom 11 (miš)[2] Bend 11 65.18 cM|11 D Početak 101,379,590 bp[2] Kraj 101,442,781 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • vezivanje tubulina • vezivanje iona metala • vezivanje enzima • vezivanje iona cinka • oštećeno vezivanje sa DNK • GO:0001948, GO:0016582 vezivanje za proteine • GO:0001105 transcription coactivator activity • androgen receptor binding • vezivanje sa RNK • ubiquitin protein ligase binding • GO:0050372 aktivnost sa transferazom ubikvitina • vezivanje sa DNK • aktivnost sa transferazom • RNA polymerase binding • vezivanje identičnih proteina Ćelijska komponenta • kompleks BRCA1-BARD1 • kondenzovani nuklearni hromosom • kompleks BRCA1-A • kompleks ubikvitin-ligaze • ćelijska membrana • nukleoplazma • kondenzovani hromosom • citoplazma • hromosom • jedro • lateralni element • GO:0009327 makromolekulani kompleks • ribonukleoprotein Biološki proces • response to ionizing radiation • centrosome cycle • hromosomska segregacija • protein K6-linked ubiquitination • intrinsic apoptotic signaling pathway in response to DNA damage • ćelijski ciklus • double-strand break repair via nonhomologous end joining • GO:0097285 apoptoza • regulation of apoptotic process • regulation of gene expression by genetic imprinting • GO:0009373 regulation of transcription, DNA-templated • negative regulation of fatty acid biosynthetic process • transcription, DNA-templated • regulation of transcription by RNA polymerase III • fatty acid biosynthetic process • regulation of DNA methylation • negative regulation of intracellular estrogen receptor signaling pathway • protein autoubiquitination • positive regulation of histone H3-K9 methylation • DNA recombination • positive regulation of angiogenesis • response to estrogen • cellular response to indole-3-methanol • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors • GO:0045996 negative regulation of transcription, DNA-templated • positive regulation of protein ubiquitination • androgen receptor signaling pathway • negative regulation of centriole replication • Postreplikacijska reparacija • lipid metabolism • cellular response to tumor necrosis factor • GO:1900404 positive regulation of DNA repair • fatty acid metabolic process • GO:1901313 positive regulation of gene expression • negative regulation of histone H3-K4 methylation • regulation of cell population proliferation • negative regulation of reactive oxygen species metabolic process • positive regulation of vascular endothelial growth factor production • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II • positive regulation of histone H4-K20 methylation • DNA double-strand break processing • double-strand break repair via homologous recombination • negative regulation of histone acetylation • protein ubiquitination • positive regulation of histone H3-K4 methylation • GO:0100026 Popravka DNK • double-strand break repair • positive regulation of histone acetylation • dosage compensation by inactivation of X chromosome • negative regulation of histone H3-K9 methylation • positive regulation of histone H3-K9 acetylation • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated • chordate embryonic development • positive regulation of histone H4-K16 acetylation • cellular response to DNA damage stimulus • protein deubiquitination • Replikacija DNK • mitotic G2/M transition checkpoint • GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II • negative regulation of G0 to G1 transition • transcription by RNA polymerase II • mitotic G2 DNA damage checkpoint signaling • regulation of signal transduction by p53 class mediator Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	672	12189
Ensembl	ENSG00000012048	ENSMUSG00000017146
UniProt	P38398	P48754
RefSeq (mRNK)	NM_007294 NM_007295 NM_007296 NM_007297 NM_007298 NM_007299 NM_007300 NM_007301 NM_007302 NM_007303 NM_007305 NM_007306	NM_009764
RefSeq (bjelančevina)	NP_009225 NP_009228 NP_009229 NP_009230 NP_009231	NP_033894
Lokacija (UCSC)	Chr 17: 43.04 – 43.17 Mb	Chr 11: 101.38 – 101.44 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

BRCA1 i BRCA2 su nepovezani proteini,^[10] ali oba se normalno eksprimiraju u ćelijama dojke i drugom tkivu, gdje pomažu u popravljanju oštećene DNK ili uništavanju ćelija, ako DNK nije moguće popraviti. Oni su uključeni u popravak hromosomskog oštećenja s važnom ulogom u nepogrešivim popravcima prekida dvolančana DNK.^[11][12] Ako su BRCA1 ili BRCA2 sami oštećeni BRCA mutacijom, oštećena DNK se ne popravlja pravilno, a to povećava rizik za rak dojke.^[13][14] BRCA1 i BRCA2 opisani su kao "geni osjetljivosti na rak dojke" i "proteini osjetljivosti na rak dojke". Prevladavajući alel ima normalnu funkciju supresije tumora, dok mutacije s visokom penetrabilnošću u ovim genima uzrokuju gubitak funkcije supresije tumora, što korelira s povećanim rizikom od raka dojke.^[15]

BRCA1 se kombinira s drugim supresorima tumora, senzorima oštećenja DNK i pretvaračima signala da bi stvorio veliki kompleks multijedinica proteina poznat kao BRCA1-asocirani kompleks za nadzor genoma (BASC).^[16] Protein BRCA1 povezuje se s RNK-polimerazom II, te putem C-terminalnog domena takođe komunicira sa kompleksima histon-deacetilaza. Dakle, ovaj protein ima ulogu u transkripciji i popravljanju prekida dvolančane DNK^[14] ubikvitinaciji, transkripcijskoj regulaciji, kao i drugim funkcijamaa.^[17]

Metodi za ispitivanje vjerovatnoće pacijenta sa mutacijama u BRCA1 i BRCA2 koje uzrokuju rak obuhvaćene su patentima u vlasništvu ili pod kontrolom Myriad Genetics. Myriadov poslovni model nuđenja dijagnostičkog testa vodio je isključivo od toga da je 1994. bio startup kompanija, koja je bila javna kompanija sa 1.200 zaposlenih i oko 500 miliona dolara godišnjeg prihoda u 2012.;^[18][19] to je također dovelo do kontroverze oko visokih cijena i nemogućnosti dobivanja drugih mišljenja od drugih dijagnostičkih laboratorija, što je zauzvrat dovelo do značajne tužbe Udruženja za molekulsku patologiju protiv Association for Molecular Pathology v. Myriad Genetics.^[20]

Otkriće

Prve dokaze o postojanju gena koji kodira enzim za obnavljanje DNK, uključenog u osjetljivost na rak dojke pružio je laboratorij Mary-Claire King na University of California, Berkeley, 1990.^[21] Četiri godine kasnije, nakon međunarodne utrke za pronalaženje ,^[22] gen su 1994. godine klonirali naučnici sa Univerziteta u Utahu, Nacionalnog instituta za nauke o zdravlju i životnoj sredini (NIEHS) i Myriad Genetics.^[23]

Lokacija gena

Ljudski gen BRCA1 nalazi se na dugom (q) kraku hromosoma 17 u području 2, opseg 1, između baznih parova 41,196.312 i 41,277.500 (Build GRCh37/hg19)^[24]Nacionalni centar za biotehnološke informacije, SAD, Nacionalna biblioteka za medicinu i ^[25] EntrezGene imaju referentne informacije za BRCA1 raka dojke 1, rani početak (Homo sapiens). Ortolozi BRCA1 identificirani su u većini kičmenjaka za koje su dostupni kompletni podaci o genomu.^[6]

Struktura proteina

Protein BRCA1 sadrži sljedeće domene:^[26]

• Cinkov prst, tip C3HC4 (RING-ov prst)
• BRCA1 C Terminus (BRCT) domain

Ovaj protein takođe sadrži motive signala jedarne lokalizacije i signala jedarnog eksporta.^[27]

Ljudski BRCA1 protein sastoji se od četiri glavna proteinska domena; Znf C3HC4- RING domen, domen BRCA1 i dva BRCT domena. Ovi domeni kodiraju približno 27% BRCA1 proteina. Poznato je šest izoformi BRCA1,^[28] sa izoformama 1 i 2 koje sadrže po 1.863 aminokiseline.

BRCA1 nije povezan sa BRCA2, tj. oni nisu homolozi ili paralozi.^[10]

Mapa domena BRCA1; označeni su RING-domeni koji sadrže serin (SCD) i BRCT. Horizontalne crne linije označavaju domene koji vežu proteine za navedene partnere. Crveni krugovi označavaju mjesta fosforilacije.^[29]

Funkcija i mehanizam

BRCA1 je dio kompleksa koji popravlja dvostruke niti u DNK. Lanci dvostruke zavojnice DNK neprekidno se lome jer se oštećuju. Ponekad je oštećen samo jedan polulanac, ponekad se oba prekidaju istovremeno. Sredstva za umrežavanje DNK važan su izvor oštećenja hromosoma/DNK. Dvolančane pukotine nastaju kao međuprodukti nakon uklanjanja umrežavanja i zaista su identificirane bialelne mutacije u BRCA1, odgovorne za Fanconijevu anemiju, komplementacijsku skupinu S,^[30] genetiku bolest povezanu sa preosjetljivošću na agense za umrežavanje DNK. BRCA1 je dio proteinskog kompleksa koji popravlja DNK kad su oštećene obje niti. Kada se to dogodi, mehanizam za popravak teško može "znati" kako zamijeniti ispravnom sekvencom DNK, a postoji više načina za pokušaj popravka. Dvolančani mehanizam za popravak u kojem sudjeluje BRCA1 je homologmo usmjereni popravak, gdje popravni proteini kopiraju identičnu sekvencu iz netaknute sestrinske hromatide.^[31]

U jedru mnogih tipova normalnih ćelija, protein BRCA1 tokom popravljanja dvonitnih preloma DNK komunicira sa RAD51.^[32] Ti prekidi mogu biti uzrokovani prirodnim zračenjem ili drugim izlaganjem, ali se mogu dogoditi i kada hromosom razmijeni genetički materijal (homologna rekombinacija, npr."krosingover" tokom mejoze). Protein BRCA2, koji ima funkciju sličnu funkciji BRCA1, također djeluje s proteinom RAD51. Utičući na sanaciju oštećenja DNK, ova tri proteina imaju ulogu u održavanju stabilnosti ljudskog genoma.

BRCA1 je također uključen u drugi tip popravke DNK, zvani popravak neusklađenosti. BRCA1 stupa u interakciju s proteinom za popravak neusklađenosti DNK MSH2.^[33] Objavljeno je da su MSH2, MSH6, PARP i neki drugi proteini koji su uključeni u popravak jednog lanca povišeni u tumorima dojke s nedostatkom BRCA1.^[34]

Protein zvani valozin-sadržavajući protein (VCP, poznat i kao p97) ima ulogu u regrutaciji BRCA1 na oštećena mjesta DNK. Nakon ionizujućeg zračenja, VCP se regrutuje u lezije DNK i sudjeluje sa ubikvitin-ligazom RNF8, kako bi se orkestrirao sklop signalnih kompleksa za efikasnu popravku DSB.^[35] BRCA1 komunicira sa VCP.^[36] BRCA1 također komunicira i s c-Myc i drugim proteinima koji su presudni za održavanje stabilnosti genoma.^[37]

BRCA1 se izravno veže za DNK, sa većim afinitetom za razgranate DNA strukture. Ova sposobnost vezanja za DNK doprinosi njenoj sposobnosti da inhibira aktivnost kompleksa nukleaza MRN, kao i aktivnost same nukleaze Mre11.^[38] Ovo može objasniti ulogu BRCA1 u podsticanju popravka DNK manje vjernosti pomoću nehomolognog spajanja krajeva (NHEJ).^[39] BRCA1 se također kolokalizira sa γ-H2AX (histon H2AX fosforiliran na serinu-139) u žarištima popravljanja dvostrukih lanaca DNK, što ukazuje da može imati ulogu u regrutovanju faktora popravka.^[17][40]

Formaldehid i acetaldehid uobičajeni su izvori poprečnih prekida DNK, često zahtijevajući popravke posredovane putem BRCA1, koji sadrži puteve.^[41]

Ova funkcija popravljanja DNK je ključna; miševi sa mutacijama gubitka funkcije u oba BRCA1 alela nisu održivi, a od 2015. godine poznato je da samo dvije odrasle osobe imaju takve mutacije; obje su imale urođene ili razvojne probleme, kao i kancer. Pretpostavljalo se da je jedna preživjela u odrasloj dobi, jer je jedna od mutacija BRCA1 bila hipomorfna.^[42]

Transkripcija

Pokazano je da BRCA1 ko-pročišćava s ljudskom RNK-polimerazom II, holoenzimom u ekstraktima HeLa, implicirajući da je komponenta holoenzima.^[43] Kasnija istraživanja, međutim, proturječila su ovoj pretpostavci, umjesto da su pokazala da je dominantni kompleks koji uključuje BRCA1 u HeLa ćelijama kompleks od dva megadaltona koji sadrži SWI/SNF.^[44] SWI / SNF je kompleks za remodeliranje hromatina. Pokazalo se da vještačko vezivanje BRCA1 za hromatin ne kondenzira heterokromatin, iako domen interakcije SWI / SNF nije bilo potreban za ovu ulogu.^[40] BRCA1 stupa u interakciju s NELF-B (COBRA1 ) podjedinica kompleksa NELF.^[40] BRCA1 je u interakciji sa NELF-B (COBRA1) podjedinicom NELF kompleksa.^[40]

Mutacije i rizik od raka

Određene varijacije gena BRCA1 dovode do povećanog rizika za raka dojke, kao dio nasljednog sindroma raka dojke-jajnika. Istraživači su identificirali stotine mutacija u genu BRCA1 , od kojih su mnoge povezane s povećanim rizikom od raka. Žene s abnormalnim genom BRCA1 ili BRCA2 imaju do 80% rizika od razvoja raka dojke do 90. godine; povećani rizik od razvoja raka jajnika je oko 55% za žene s BRCA1 mutacijama i oko 25% za žene s mutacijama BRCA2.^[45]

Ove mutacije mogu biti promjene na jednom ili malom broju baznih parova DNK (građevni blokovi DNK) i mogu se identificirati pomoću PCR-a i sekvenciranja DNK.

U nekim slučajevima se preuređuju veliki segmenti DNK. Ti veliki segmenti, koji se nazivaju i velikim rearanžmanima, mogu biti delecija ili duplikacija jednog ili nekoliko egzona u genu. Klasični metodi za otkrivanje mutacija (sekvenciranje) nisu u stanju da otkriju ove tipove mutacija.^[46] Predloženi su i drugi metodi: standardna kvantitativna PCR-analiza,^[47] multipleks ligacijski-ovisne sonde (MLPA),^[48] i kvantitativni multipleksni PCR kratkih fluorescentnih fragmenata (QMPSF).^[49] Nedavno su predložene i novije metode: heterodupleksna analiza (HDA) multikapilarnom elektroforezom ili također namjenskim sekvenciranjem oligonukleotida, zasnovanom na upordnoj hibridizaciji genoma (mreža-CGH).^[50]

Neki rezultati sugeriraju da bi se hipermetilacija promotora BRCA1, koji je prijavljen kod nekih karcinoma, mogao smatrati mehanizmom za inaktivaciju ekspresije BRCA1.^[51]

Mutirani gen BRCA1 obično stvara protein koji ne funkcionira pravilno. Vjeruje se da neispravni protein BRCA1 nije u stanju pomoći u popravljanju oštećenja DNK, što dovodi do mutacija drugih gena. Ove mutacije mogu se akumulirati i omogućiti ćelijama nekontrolirani rast i dijeljenje, kako bi stvorile tumor. Dakle, inaktivacijske mutacije BRCA1 dovode do predispozicije za rak.

BRCA1 iRNK 3'UTR može biti vezana za miRNK, Mir-17 mikroRNK. Sugerira se da bi varijacije ove miRNA zajedno sa Mir-30 mikroRNK mogle izazvati osjetljivost na rak dojke.^[52]

Pored karcinoma dojke, mutacije gena BRCA1 takođe povećavaju rizik od karcinoma jajnika i prostate. Šta više, prekancerozne lezije (displazija) unutar jajovoda povezane su s mutacijama gena BRCA1. Patogene mutacije bilo gdje u putevima modela koji sadrže BRCA1 i BRCA2 uveliko povećavaju rizike za podskupinu leukemija i limfoma.

Žene koje su naslijedile neispravan gen BRCA1 ili BRCA2 uveliko imaju povećan rizik od razvoja karcinoma dojke i jajnika. Njihov rizik od razvoja karcinoma dojke i/ili jajnika toliko je visok i toliko je specifičan za te karcinome da se mnogi nositelji mutacija odluče na profilaksnu operaciju. Bilo je mnogo nagađanja koja objašnjavaju tako očigledno zapanjujuću specifičnost tkiva. Glavne odrednice gdje se javljaju nasljedni karcinomi BRCA1/2 povezane su sa tkivnom specifičnošću patogena raka, agensa koji uzrokuje hroničnu upalu ili karcinogenezu. Ciljno tkivo može imati receptore za patogen, može biti selektivno izloženo upalnom procesu ili karcinogenu. Urođeni genomski u nedostatak gena za supresiju tumora narušava normalne reakcije i pogoršava osjetljivost na bolesti u organima- metama. Ova teorija također uklapa podatke za nekoliko tumorskih supresora izvan BRCA1 ili BRCA2. Glavna prednost ovog modela je u tome što sugerira da se uz profilaksnu operaciju mogu obaviti i neke druge opcije.^[53]

Mutacija BRCA1 u raku dojke i jajnika

Samo oko 3% –8% svih žena s rakom dojke ima mutaciju u BRCA1 ili BRCA2.^[54] Slično tome, mutacije BRCA1 nađene su samo kod oko 18% karcinoma jajnika (13% mutacija zametnih linija i 5% somatskih mutacija).^[55]

Prema tome, dok je ekspresija BRCA1 kod većine ovih karcinoma niska, mutacija BRCA1 nije glavni uzrok smanjene ekspresije. Određeni latentni virusi, koji se često otkrivaju u tumorima raka dojke, mogu smanjiti ekspresiju gena BRCA1 i izazvati razvoj tumora dojke.^[56]

Karcinom dojke (uključujući i muški): Međuodnosi fenotip – genotip^[57][58][59]

Lokacija	Fenotip	Fenotipski MIM broj	Nasljeđivanje + oznaka mutacije	Ključ fenotipskog mapiranja	Oznaka lokusa	Genski/lokusni MIM broj
1p34.1	Invazivni duktusni	114480	AD*, SMu	3	RAD54L	603615
2q33.1	Zaštitni	114480	AD, SMu	3	CASP8	601763
2q35	Podložnost	114480	AD, SMu	3	BARD1	601593
3q26.32	Somatski	114480		3	PIK3CA	171834
5q34	Podložnost	114480	AD, SMu	3	HMMR	600936
6p25.2	Podložnost (?)	114480	AD, SMu	1	NQO2	160998
6q25 1-q25.2	Somatski	114480		3	ESR1	133430
8q11.23	Somatski	114480		3	RB1CC1	606837
11p15.4	Somatski	114480		3	SLC22A1L	602631
11q22.3	Podložnost	114480	AD, SMu	3	ATM	607585
12p12.1	Somatski	114480		3	KRAS	190070
13q13.1	Podložnost, muški	114480	AD, SMu	3	BRCA2	600185
14q32.33	Podložnost	114480	AD, SMu	3	XRCC3	600675
14q32.33	Somatski	114480		3	AKT1	164730
15q15.1	Podložnost	114480	AD, SMu	3	RAD51	179617
16p12.2	Podložnost	114480	AD, SMu	3	PALB2	610355
16q22.1	Režanjski	114480	AD, SMu	3	CDH1	192090
17q21.33	Podložnost	114480	AD, SMu	3	PHB	176705
17p13.1	Somatski	114480		3	TP53	191170
17q23.2	Somatski	114480		3	PPM1D	605100
17q23.2	Ranopojavna podložnost	114480	AD, SMu	3	BRIP1	605882
22q12.1	Podložnost	114480	AD, SMu	3	CHEK2	604373

• AD = Autosomno dominantno nasljeđivanje

Promotorska hipermetilacija BRCA1 u raku dojke i jajnika

Promotorska hipermetilacija BRCA1 bila je prisutan u samo 13% neizabranih primarnih karcinoma dojke.^[60] Slično tome, hipermetilacija promotora BRCA1 bila je prisutna u samo 5% do 15% slučajeva EOC-a.

Dakle, dok je ekspresija BRCA1 kod ovih karcinoma niska, metilacija promotora BRCA1 samo je manji uzrok smanjene ekspresije.

MikroRNK represija BRCA1 kod karcinoma dojke

Postoji niz specifičnih mikroRNK, , koje, kada su prekomerno eksprimirane, direktno smanjuju ekspresiju specifičnih proteina koji popravljaju DNK (vidi mikroRNK, odjeljak: popravak DNK i rak). U slučaju raka dojke, mikroRNK-182 (miR-182) specifično cilja BRCA1.^[61] Rak dojke može se klasificirati na osnovu statusa receptora ili histoloških obilježja, u trostruko negativni rak dojke (15% –25% karcinoma dojke), HER2 + (15% –30% karcinoma dojke), ER + / PR + (oko 70% karcinoma dojke) i Invazivni režanjski karcinom (oko 5% –10% invazivnog karcinoma dojke). Utvrđeno je da sva četiri tipa karcinoma dojke u prosjeku imaju oko 100 puta veći porast miR-182 u odnosu na normalno tkivo dojke.^[62] U ćelijskim linijama karcinoma dojke postoji inverzna korelacija nivoa proteina BRCA1 sa ekspresijom miR-182. Stoga se čini da je velik dio smanjenja ili odsustva BRCA1 kod duktusnih karcinoma dojke visokog stepena prekomjerno eksprimirani miR-182.

Pored miR-182, par gotovo identičnih mikroRNK, miR-146a i miR-146b-5p, također potiskuju ekspresiju BRCA1. Ove dvije mikroRNK su prekomjerno eksprimirane u trostruko negativnim tumorima i njihova prekomjerna ekspresija rezultira inaktivacijom BRCA1. Dakle, miR-146a i / ili miR-146b-5p mogu također doprinijeti smanjenoj ekspresiji BRCA1 kod ovih trostruko negativnih karcinoma dojke.

MikroRNK represija BRCA1 kod karcinoma jajnika

I u seroznim tubulskim intraepitelnim karcinomima (prethodnica lezije visokoeksprimiranog seroznog karcinoma jajnika (HG-SOC)), i u samom HG-SOC, miR- 182 je prekomjerno eksprimiran u oko 70% slučajeva.^[63] Dakle, miR-146a i / ili miR-146b-5p mogu takođe doprinijeti smanjenoj ekspresiji BRCA1 kod ovih trostruko negativnih karcinoma dojke.

Još jedna mikroRNK za koju je poznato da smanjuje ekspresiju BRCA1 u ćelijamama raka jajnika je miR-9. Među 58 tumora pacijenata sa stadijem IIIC ili stadijem IV seroznog karcinoma jajnika (HG-SOG), pronađena je inverzna korelacija između ekspresija miR-9 i BRCA1, tako da povećani miR-9 kod ovih karcinoma jajnika također može doprinijeti smanjenoj ekspresiji BRCA1.

Nedostatak ekspresije BRCA1 – vjerovatno tumorogen

Oštećenje DNK je primarni uzrok raka,^[64] a izgleda da su nedostaci u popravljanju DNK u osnovi mnogih oblika raka.^[65] Ako je popravak DNK nedostatan, oštećenje DNK se akumulira. Takav višak oštećenja DNK može povećati mutacijske greške tokom replikacije zbog sklonosti greškama sintezi translezije. Prekomjerna oštećenja DNK mogu također povećati epigenetičke promjene, zbog grešaka tokom popravka DNK.^[66][67] Takve mutacije i epigenetičke promjene mogu dovesti do karcinoma. Česti nedostatak BRCA1 izazvan mikroRNK kod karcinoma dojke i jajnika vjerovatno pridonosi njihovom napredovanju.

Populacija ili podrrupa	Mutacija BRCA1[68]	Reference
Afroamerikanci	943ins10, M1775R	[69]
Afrikanci	E881X, 1374delC	[70][71]
Aškenazi Jevreji	185delAG, 188del11, 5382insC	[72][73]
Austrijanci	2795delA, C61G, 5382insC, Q1806stop	[74]
Belgijanci	2804delAA, IVS5+3A>G	[75][76]
Nizozemci	Delecija egzona 2, delecija egzona 3, 2804delAA	[75][77][78]
Finci	3745delT, IVS11-2A>G	[79][80]
Francuzi	3600del11, G1710X	[81]
Francuski Kanađani	C4446T	[82]
Nijemci	5382insC, 4184del4	[83][84]
Grci	5382insC	[85]
Mađari	300T>G, 5382insC, 185delAG	[86]
Italijani	5083del19	[87]
Japanci	L63X, Q934X	[88]
Autohtoni Amerikanci	1510insG, 1506A>G	[89]
Sjeverni Irci	2800delAA	[90]
Norvežani	816delGT, 1135insA, 1675delA, 3347delAG	[91][92]
Pakistanci	2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G	[93]
Poljaci	300T>G, 5382insC, C61G, 4153delA	[94][95]
Rusi	5382insC, 4153delA	[96]
Škoti	2800delAA	[90][97]
Španci	R71G	[98][99]
Šveđani	Q563X, 3171ins5, 1201del11, 2594delC	[69][100]

Hemoterapija kancera

Nemaloćelijski rak pluća (NSCLC) vodeći je uzrok smrti od raka u svijetu. Pri dijagnozi, gotovo 70% osoba s NSCLC ima lokalno uznapredovalu ili metastatsku bolest. Osobe s NSCLC često se liječe terapijskim spojevima platine (npr. cisplatinom, karboplatinom ili oksaliplatinom) koji uzrokuju međulančane unakrsne veze u DNK. Među osobama s NSCLC, niska ekspresija BRCA1 u primarnom tumoru korelirala je s poboljšanim preživljavanjem nakon hemoterapije koja sadrži platinu.^[101][102] Ova korelacija implicira da nizak BRCA1 u karcinomu i posljedično nizak nivo popravljanja DNK uzrokuju ranjivost raka na liječenje pomoću DNK agenasa za umrežavanje. Visok BRCA1 može zaštititi ćelije raka, djelujući na put koji uklanja oštećenja u DNK koju unose lijekovi od platine. Stoga je nivo ekspresije BRCA1 potencijalno važan alat za prilagođavanje hemoterapije u upravljanju karcinomom pluća.

Nivo ekspresije BRCA1 je također važan za liječenje raka jajnika. Pacijenti sa sporadičnim karcinomom jajnika koji su liječeni lijekovima od platine imali su duže medijane vremena preživljavanja ako je njihova ekspresija BRCA1 bila niska u odnosu na pacijente sa jačom ekspresijom BRCA1 (46 u odnosu na 33 mjeseca).^[103]

Interakcije

Pokazalo se da BRCA1 komunicira sa sljedećim proteinima:

• ABL1^[104]
• AKT1^[105][106]
• AR^[107]
• ATR^{[108][109][110][111]}
• ATM^{[16][108][109][110][111][112][113]}
• ATF1^[114]
• BACH1^[115]
• BARD1^{[33][37][115]}
• BRCA2^{[116][117][118][119]}
• BRCC3^[116]
• BRE^[116]
• BRIP1^{[120][121][122][123][124]}
• C-jun^[125]
• CHEK2^[126][127]
• CLSPN^[128]
• COBRA1^[129]
• CREBBP^{[130][131][132][133][134]}
• CSNK2B^[135]
• CSTF2^[136][137]
• CDK2^{[138][139][140]}
• DHX9^[141][142]
• ELK4^[143]
• EP300^[131][133]
• ESR1^{[133][144][145][146]}
• FANCA^[147]
• FANCD2^[118][148]
• FHL2^[149][150]
• H2AFX^{[151][152][153]}
• JUNB^[125]
• JunD^[125]
• LMO4^[154][155]
• MAP3K3^[156]
• MED1^[121]
• MED17^{[121][157][158]}
• MED21^[159]
• MED24^[121]
• MRE11A^{[16][157][160][161]}
• MSH2^[16][33]
• MSH3^[33][120]
• MSH6^[16][33]
• Myc^{[37][162][163][164]}
• NBN^{[16][157][160]}
• NMI^[162]
• NPM1^[165]
• NCOA2^[120][166]
• NUFIP1^[167]
• P53^{[116][132][168][169][170]}
• PALB2^[171]
• POLR2A^{[157][159][172][173]}
• PPP1CA^[174]
• Rad50^{[16][157][160]}
• RAD51^{[33][116][117][175]}
• RBBP4^[176]
• RBBP7^{[176][177][178]}
• RBBP8^{[120][179][180][181][182][183][184]}
• RELA^[130]
• RB1^{[176][185][186]}
• RBL1^[185]
• RBL2^[185]
• RPL31^[178]
• SMARCA4^[187][188]
• SMARCB1^[187]
• STAT1^[189]
• UBE2D1^{[116][148][151][152][165][190][191][192][193][194]}
• USF2^[195]
• VCP^[196]
• XIST^[197][198] i
• ZNF350^[199]

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Vanjski linkovi

• BRCA1 Protein na US National Library of Medicine Medical Subject Headings (MeSH)
• Genes, BRCA1 na US National Library of Medicine Medical Subject Headings (MeSH)
• PDBe-KB pruža pregled svih informacija o strukturi dostupnih u PDB za ljudsku BRCA1.