Proliferirajući ćelijski jedarni antigen

(Preusmjereno sa PCNA)

Proliferirajući ćelijski jedarni antigen (PCNA) je DNK-stezaljka koja djeluje kao procesivni faktor za DNK-polimerazu δ u eukariotske ćelije i neophodan je za replikaciju. PCNA je homotrimer i svoju procesnost postiže okružujući DNK, gdje djeluje kao skela za regrutovanje proteina uključenih u replikaciju DNK, popravak DNK, remodeliranje hromatina i epigenetičke uticaje. Kod ljudi, genski lokus PCNA nalazi se na kratkom (p) kraku hromosoma 20.[5]

PCNA
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

4D2G, 1AXC, 1U76, 1U7B, 1UL1, 1VYJ, 1VYM, 1W60, 2ZVK, 2ZVL, 2ZVM, 3P87, 3TBL, 3VKX, 3WGW, 4RJF, 3JA9, 4ZTD, 5IY4, 5E0U, 5E0T, 5E0V

Identifikatori
AliasiPCNA
Vanjski ID-jeviOMIM: 176740 MGI: 97503 HomoloGene: 1945 GeneCards: PCNA
Lokacija gena (čovjek)
Hromosom 20 (čovjek)
Hrom.Hromosom 20 (čovjek)[1]
Hromosom 20 (čovjek)
Genomska lokacija za PCNA
Genomska lokacija za PCNA
Bend20p12.3Početak5,114,953 bp[1]
Kraj5,126,626 bp[1]
Lokacija gena (miš)
Hromosom 2 (miš)
Hrom.Hromosom 2 (miš)[2]
Hromosom 2 (miš)
Genomska lokacija za PCNA
Genomska lokacija za PCNA
Bend2 F2|2 64.15 cMPočetak132,091,082 bp[2]
Kraj132,095,234 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija MutLalpha complex binding
vezivanje identičnih proteina
vezivanje enzima
receptor tyrosine kinase binding
vezivanje sa DNK
DNA polymerase binding
oštećeno vezivanje sa DNK
dinucleotide insertion or deletion binding
GO:0001948, GO:0016582 vezivanje za proteine
chromatin binding
histone acetyltransferase binding
estrogen receptor binding
purine-specific mismatch base pair DNA N-glycosylase activity
DNA polymerase processivity factor activity
Ćelijska komponenta jedro
Replisom
nukleoplazma
Egzosom
DNA replication factor C complex
centrosom
PCNA complex
nuclear replication fork
PCNA-p21 complex
replication fork
nuclear body
Hromatin
Biološki proces replication fork processing
translesion synthesis
Replikacija DNK
nucleotide-excision repair, DNA gap filling
protein sumoylation
regulation of DNA replication
transcription-coupled nucleotide-excision repair
positive regulation of deoxyribonuclease activity
nucleotide-excision repair, DNA incision
error-free translesion synthesis
GO:1900404 positive regulation of DNA repair
regulation of transcription involved in G1/S transition of mitotic cell cycle
positive regulation of DNA replication
response to lipid
heart development
Popravak neusklađenosti DNK
cellular response to DNA damage stimulus
mitotic telomere maintenance via semi-conservative replication
epithelial cell differentiation
response to cadmium ion
Ćelijska proliferacija
telomere maintenance
error-prone translesion synthesis
cellular response to UV
estrous cycle
cellular response to hydrogen peroxide
response to dexamethasone
nucleotide-excision repair, DNA incision, 5'-to lesion
liver regeneration
response to estradiol
GO:0001306 response to oxidative stress
GO:0100026 Popravka DNK
response to L-glutamate
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
DNA ligation
leading strand elongation
protein ubiquitination
telomere maintenance via semi-conservative replication
GO:0022415 viral process
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_182649
NM_002592

NM_011045

RefSeq (bjelančevina)

NP_002583
NP_872590

NP_035175

Lokacija (UCSC)Chr 20: 5.11 – 5.13 MbChr 2: 132.09 – 132.1 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš
Cryo-EM struktura procesivnog kompleksa PolD–PCNA vezanog za DNK

Mnogi proteini stupaju u interakciju sa PCNA preko dva poznata PCNA-interagirajuća motiva PCNA-interaktivne peptidne (PIP) kutije [6] i AlkB homolog 2 PCNA motiva u interakciji (APIM).[7] Proteini koji se vezuju za PCNA preko PIP-kutije su uglavnom uključeni u replikaciju DNK, dok su proteini koji se vezuju za PCNA preko APIM-a uglavnom važni u kontekstu genotoksičnog stresa.[8]

Funkcija uredi

Protein koji je kodiran ovim genom nalazi se u jedru i kofaktor je delta DNK-polimeraza. Kodirani protein djeluje kao homotrimer i pomaže u povećanju procesivnosti sinteze vodećeg lanca tokom replikacije DNK. Kao odgovor na oštećenje DNK, ovaj protein je ubikvitinski uključen, kao i u RAD6-ovisni put popravk DNK. Za ovaj gen su pronađene dvije varijante transkripta koje kodiraju isti protein. Pseudogeni ovog gena su opisani na hromosomu 4 i na hromosomu X.[9]

PCNA se također nalazi u arhejama, kao faktor procesivnosti polD, jedinstvene multifunkcionalne DNK-polimeraze u ovoj domeni života.[10]

Ekspresija u jedru tokom sinteze DNK uredi

PCNA je prvobitno identifikovana kao antigen koji se eksprimira u ćelijskom jedru tokom faze sinteze DNK ćelijskog ciklusa. Dio proteina je sekvenciran i ta sekvenca je korištena da se omogući izolacija klona cDNK.[11] PCNA pomaže u držanju DNK-polimeraze delta (Pol δ) na DNK. PCNA je stegnut [12][13] koji je heteropentamerni član AAA+ klase ATPaza. Ekspresija PCNA je pod kontrolom kompleksa koji sadrže E2F transkripcijski faktor.[14][15]

Uloga u popravku DNK uredi

Budući da je DNK-polimeraza epsilon uključena u resintezu izrezanih oštećenih lanaca DNK tokom popravka DNK, PCNA je važna i za sintezu DNK i za popravak DNK.[16][17]

PCNA je također uključen u put tolerancije oštećenja DNK poznat kao replikacijski popravak (PRR).[18] U PRR postoje dva potputa: (1) put translezije, koji se provodi specijaliziranim DNK-polimerazama koje su sposobne da inkorporiraju oštećene baze DNK u svoja aktivna mjesta (za razliku od normalne replikativne polimeraze, koja se zaustavlja), i time zaobilaze oštećenje, i (2) predloženi put "prebacivanja šablona" za koji se smatra da uključuje premoštavanje oštećenja angažovanjem mehanizma za homolognu rekombinaciju. PCNA je ključan za aktivaciju ovih puteva i izbor koji put će ćelija koristiti. PCNA postaje posttranslacijski modificiran pomoću ubikvitina.[19] Monoubikvitin lizina broj 164 na PCNA aktivira put sinteze translezije. Smatra se da proširenje ovog monoubikvitina pomoću nekanonskog lanca poliubikvitina vezanog uz lizin-63 na PCNA[19] aktivira put prebacivanja šablona. Nadalje, sumoilacija (pomoću malog modifikatora sličnog ubikvitinu, SUMO) PCNA lizina-164 (i u manjoj mjeri, lizina-127) inhibira put prebacivanja šablona.[19] Ovaj antagonistički efekt nastaje jer sumoilirana PCNA regrutuje DNK-helikazu zvanu Srs2,[20] koja ima ulogu u razbijanju Rad51 nukleoproteinskih filamenata koji su fundamentalni za iniciranje homologne rekombinacije.

PCNA-vezujući proteini uredi

PCNA stupa u interakciju s mnogim proteinima.[21]

Interakcije uredi

Pokazalo se da PCNA interraguje sa:

Proteini koji komuniciraju sa PCNA preko APIM-a uključuju ljudski AlkB homolog 2, TFIIS-L, TFII-I, Rad51B,[7] XPA,[87] ZRANB3,[88] and FBH1.[89]

Upotreba uredi

Antitijela protiv proliferirajućeg ćelijskog jedarnog antigena (PCNA) ili monoklonsko antitijelo zvano Ki-67 može se koristiti za procjenu različitih neoplazmi, npr. astrocitoma. Mogu imati dijagnostičku i prognostičku vrijednost. Snimanje jedarne distribucije PCNA (putem označavanja antitijela) može se koristiti za razlikovanje između ranog, srednje i kasne S-faze ćelijskog ciklusa.[90] Međutim, važno ograničenje antitijela je da ćelije moraju biti fiksirane što dovodi do potencijalnih artefakata.

S druge strane, proučavanje dinamike replikacije i popravke u živim ćelijama može se obaviti uvođenjem translacijskih fuzija PCNA. Da bi se eliminisala potreba za transfekcijama i zaobišao problem ćelija koje je teško transficirati i/ili kratko žive, mogu se koristiti markeri za replikaciju i/ili reparaciju permeabilnih ćelija. Ovi peptidi nude izrazitu prednost koja se može koristiti "in situ" u živom tkivu i čak razlikovati ćelije koje su podvrgnute replikaciji od ćelija koje su podvrgnute popravljanju..[91]

PCNA je potencijalna terapijska meta u terapiji kancera.[92]

Također pogledajte uredi

Reference uredi

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