Proliferirajući ćelijski jedarni antigen

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

5111

18538

Ensembl

ENSG00000132646

ENSMUSG00000027342

UniProt

P12004

P17918

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

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]

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

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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

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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

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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

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PCNA stupa u interakciju s mnogim proteinima.[21]

Interakcije

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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

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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

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Reference

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