Antíxeno nuclear de célula proliferante

O antíxeno nuclear de célula proliferante ou PCNA (do inglés Proliferating cell nuclear antigen) é unha abrazadeira do ADN que actúa como factor de procesividade para a ADN polimerase δ nas células eucariotas e é esencial para a replicación do ADN. O PCNA é un homotrímero (formado por tres unidades PCNA) e debe a súa procesividade a que rodear o ADN como un anel ou abrazadeira, onde actúa como un armazón que recruta proteínas implicadas na replicación do ADN, reparación do ADN, remodelación da cromatina e na epixenética.^[1]

A abrazadeira do ADN humana ensamblada é un trímero da proteína PCNA.
Antíxeno nuclear de célula proliferante (Proliferating cell nuclear antigen, PCNA)
Identificadores
Símbolo	PCNA
Símbolos alt.	ATLD2
Entrez	5111
OMIM	176740
RefSeq	NP_002583
UniProt	P12004
Outros datos
Locus	Cr. 20 :(5.11 – 5.13 Mb)

Co PCNA interaccionan moitas proteínas por medio dos chamados motivo de interacción do PCNA, caixa do péptido que interacciona co PCNA (PIP box) ^[2] e motivo que interaccióna co PCNA homólogo 2 de AlkB (APIM, AlkB homologue 2 PCNA interacting motif).^[3] As proteínas que se unen ao PCNA por medio da caixa PIP están implicadas principalmente na replicación do ADN, mentres que aquelas que se unen ao PCNA por medio do APIM son importantes principalmente no contexto do estrés xenotóxico.^[4]

Función

En humanos esta proteína está codificada polo xene PCNA do cromosoma 20. A proteína codificada por este xene encóntrase no núcleo e é un cofactor da ADN polimerase delta. A proteína codificada actúa como homotrímero e axuda a incrementar a procesividade da síntese na febra guía durante a replicación do ADN. En resposta aos danos no ADN, esta proteína é ubiquitinada e está implicada na vía de reparacion do ADN dependente de RAD6. Atopáronse dúas variantes de transcrición desta proteína codificadas no mesmo xene. Ademais, describíronse pseudoxenes deste xene nos cromosomas 4 e X.^[5]

Expresión no núcleo durante a síntese de ADN

O PCNA foi identificado orixinalmente como un antíxeno que se expresaba no núcleo celular durante a fase S (de síntese de ADN) do ciclo celular, de aí o seu nome.^[6] Parte da proteína foi secuenciada e esa secuencia foi utilizada para despois illar un clon de ADNc.^[7] O PCNA axuda a manter a ADN polimerase epsilon (Pol ε) no ADN. O PCNA agárrase ^[8] ao ADN grazas á acción do factor de replicación C (RFC),^[9] o cal é un membro heteropentamérico da clase AAA+ de ATPases. A expresión de PCNA está baixo o control de complexos que conteñen o factor de transcrición E2F.^[10]

Función na reparación do ADN

Como a ADN polimerase epsilon está implicada na resíntese das febras de ADN danadas escindidas durante a reparación do ADN, o PCNA é importante tanto para a síntese de ADN coma para a reparación do ADN.^[11][12]

O PCNA intervén tamén na vía de tolerancia aos danos no ADN chamada reparación post-replicación (PRR).^[13] Na reparación post-replicación hai dúas subvías: (1) a vía translesión, que é levada a cabo por ADN polimerases especializadas que teñen a capacidade de incorporar bases de ADN danado nos seus sitios activos (a diferenza as polimerase replicativa normal, que queda bloqueada), e dese xeito pode sortear a zona danada, e (2) unha vía proposta chamada de "cambio de molde" (template switch), que se cre está implicada en pasar pola zona danada ao recrutar a maquinaria da recombinación homóloga.

O PCNA ten un papel central na activación destas vías e na elección de que vía será utilizada pola célula. O PCNA é modificado postraducionalmente pola ubiquitina.^[14] A monoubiquitina unida á lisina número 164 do PCNA activa a vía de síntese translesión. A extensión desta monoubiquitina por unha cadea de poliubiquitina unida á lisina 63 non canónica no PCNA^[14] pénsase que activa a vía de cambio de molde. Ademais, a sumoilación (por pequenas proteínas modificadoras parecidas á ubiquitina chamadas SUMO) da lisina 164 do PCNA (e en menor medida da lisina 127) inhibe a vía de cambio de molde.^[14] Este efecto antagónico ocorre porque o PCNA sumoilado recruta unha ADN helicase chamada Srs2,^[15] que ten un papel na distorsión dos filamentos da nucleoproteína Rad51, que é fundamental para a iniciación da recombinación homóloga.

Proteínas que se unen ao PCNA

Dominio proteico TCP  • receptor NKp44  • procaspases ^[16]  • ADN polimerases  • cargador da abrazadeira  • endonuclease flap  • ADN ligase  • topoisomerase  • factor autorizador da replicación (replication licensing factor)  • ubiquitina ligases E3  • encima conxugador de SUMO E2  • helicases, ATPases  • encimas de reparación de discordancias (apareamentos de bases non complementarias)  • encimas de reparación de excisión de bases  • encima de reparación da excisión de nucleótidos  • poli ADP ribosa polimerase  • chaperona de histona  • factor remodelador da cromatina  • histona acetiltransferase  • histona desacetiltransferase  • ADN metiltransferase  • factores de cohesión das cromátides irmás  • proteína quinases  • reguladores do ciclo celular  • factores apoptóticos.

Para máis detalles ver ^[17].

Interaccións

O PCNA presenta interaccións con:

• Anexina A2,^[18]
• CDC25C,^[19]
• CHTF18,^[18]
• Ciclina D1,^[20][21]
• Ciclina O,^[18][22]
• Quinase dependente de ciclina 4,^[21][23]
• Inhibidor da quinase dependente de ciclicna 1C,^[24]
• DNMT1,^[25][26][27]
• EP300,^[28]
• Endonuclease específica da estrutura flap 1,^{[29][30][31][32][33][34][35]}
• GADD45A,^{[36][37][38][39][40]}
• GADD45G,^[41][42]
• HDAC1,^[43]
• HUS1,^[44]
• ING1,^[45]
• KCTD13,^[46]
• KIAA0101,^[35]
• Ku70,^[18][47]
• Ku80,^[18][47][48]
• MCL1,^[49]
• MSH3,^[18][50][51]
• MSH6,^[18][50][51]
• MUTYH,^[52]
• P21,^{[24][31][35][53][54][55][56][57]}
• POLD2,^[58]
• POLD3,^[18][59]
• POLDIP2,^[60]
• POLH,^[61]
• POLL,^[62][63][64]
• RFC1,^{[18][53][65][66][67]}
• RFC2,^[18][68][69]
• RFC3,^[18][70]
• RFC4,^[18][68]
• RFC5,^[18][66][68]
• Ubiquitina C^[71][72][73]
• Helicase dependente de ATP da síndrome de Werner,^[74][75]
• XRCC1,^[76] and
• Proteína de unión á caixa Y 1.^[77]

Entre as proteínas que interaccionan co PCNA por medio de APIM están o homólogo 2 de AlkB humano, TFIIS-L, TFII-I, Rad51B,^[3] XPA,^[78] ZRANB3,^[79] e FBH1.^[80]

Usos

Poden utilizarse anticorpos contra o PCNA ou o anticorpo monoclonal denominado Ki-67 para clasificar diferentes neoplasmas, por exemplo, o astrocitoma. Poden ser útiles tamén para facer diagnósticos e prognósticos. As imaxes da distribución nuclear do PCNA (por medio de etiquetado de anticorpos) poden utilizarse para distinguir entre as fase S temperá, media ou tardía do ciclo celular.^[81] Porén, unha importante limitación deste uso dos anticorpos é que as células necesitan ser fixadas o que pode producir artefactos.

Por outra parte, o estudo da dinámica da replicación e reparación en células vivas pode facerse introducindo fusións traducionais do PCNA. Para obviar a necesidade de transfección e sortear o problema da dificultade que hai para transfectar e a curta vida das células, pode usarse a replicación permeable de células e os marcadores de reparación. Estes péptidos ofrecen a clara vantaxe de que poden utilizarse in situ en tecidos vivos e mesmo poden distinguirse as células en replicación das células en reparación.^[82]

O PCNA é unha diana terapéutica potencial na terapia do cancro.^[83]

Notas

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4. Mailand N, Gibbs-Seymour I, Bekker-Jensen S (maio de 2013). "Regulation of PCNA-protein interactions for genome stability.". Nature reviews. Molecular cell biology 14 (5): 269–82. PMID 23594953. doi:10.1038/nrm3562.
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Véxase tamén

Outros artigos

• Abrazadeira do ADN
• Transcrición
• Ki-67, marcador celular de proliferación

Ligazóns externas

• PCNA Medical Subject Headings (MeSH) na Biblioteca Nacional de Medicina dos EUA.
• "ANA: Cell cycle related (Mitotic): PCNA type 1 and type 2 Antibody Patterns". Antibody Patterns.com. Arquivado dende o orixinal o 23 de setembro de 2015. Consultado o 2008-04-15.
• Dan Krotz. "Structure of a clamp–loader complex". Advanced Light Source News. Lawrence Berkeley National Laboratory. Consultado o 2008-04-15.
• "Movie showing a model of clamp loading of PCNA onto DNA". Pubmed Central.^{[Ligazón morta]}
• Miyata T, Suzuki H, Oyama T, Mayanagi K, Ishino Y, Morikawa K (2005). "Open clamp structure in the clamp-loading complex visualized by electron microscopic image analysis". Proc. Natl. Acad. Sci. U.S.A. 102 (39): 13795–13800. PMC 1236569. PMID 16169902. doi:10.1073/pnas.0506447102.</ref>

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