PARP1: Diferenzas entre revisións

A PARP1 ten unha función da reparación das roturas de febra simple no ADN. Se realizamos un [[knockdown de xenes|knock-down]] dos niveis intracelulares de PARP1 usando un [[ARN interferente pequeno]] ou inhibindo a actividae da PARP1 cunha pequena molécula, isto causa a redución da reparación das roturas de febra simple. En ausencia de PARP1, cando se encontra unha destas roturas durante a [[replicación do ADN]], a [[forcada de replicación]] queda atascada, e acumúlanse roturas de dobre febra no ADN. Estas roturas de dobre febra son reparadas por [[recombinación homóloga]], un mecanismo de reparación xeralmente libre de erros. Por esta razón, as células que carecen de PARP1 mostran un [[fenotipo]] hiperrecombinaxénico (por exemplo, un incremento da frecuencia de [[recombinación homóloga]]),<ref name="pmid18603595">{{cite journal | vauthors = Godon C, Cordelières FP, Biard D, Giocanti N, Mégnin-Chanet F, Hall J, Favaudon V | title = PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility | journal = Nucleic Acids Research | volume = 36 | issue = 13 | pages = 4454–64 | date = Aug 2008 | pmid = 18603595 | pmc = 2490739 | doi = 10.1093/nar/gkn403 }}</ref><ref name="pmid12930944">{{cite journal | vauthors = Schultz N, Lopez E, Saleh-Gohari N, Helleday T | title = Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination | journal = Nucleic Acids Research | volume = 31 | issue = 17 | pages = 4959–64 | date = Sep 2003 | pmid = 12930944 | pmc = 212803 | doi = 10.1093/nar/gkg703 }}</ref><ref name="pmid1945881">{{cite journal | vauthors = Waldman AS, Waldman BC | title = Stimulation of intrachromosomal homologous recombination in mammalian cells by an inhibitor of poly(ADP-ribosylation) | journal = Nucleic Acids Research | volume = 19 | issue = 21 | pages = 5943–7 | date = Nov 1991 | pmid = 1945881 | pmc = 329051 | doi = 10.1093/nar/19.21.5943 }}</ref> o cal foi observado en vivo en ratos.<ref name="pmid20660013">{{cite journal | vauthors = Claybon A, Karia B, Bruce C, Bishop AJ | title = PARP1 suppresses homologous recombination events in mice in vivo | journal = Nucleic Acids Research | volume = 38 | issue = 21 | pages = 7538–45 | date = Nov 2010 | pmid = 20660013 | pmc = 2995050 | doi = 10.1093/nar/gkq624 }}</ref> Deste xeito, se a vía da recombinación homóloga está funcionando, os [[mutante nulo|mutantes nulos]] de PARP1 (células nas que non funciona PARP1) non mostran un fenotipo enfermo, e, de feito, os [[rato knockout|ratos knock-out]] para PARP1 non mostran fenotipo negativo nin incremento da incidencia da formación de tumores.<ref name="pmid7698643">{{cite journal | vauthors = Wang ZQ, Auer B, Stingl L, Berghammer H, Haidacher D, Schweiger M, Wagner EF | title = Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease | journal = Genes & Development | volume = 9 | issue = 5 | pages = 509–20 | date = Mar 1995 | pmid = 7698643 | doi = 10.1101/gad.9.5.509 }}</ref>

 

 

 

A PARP1 tamén se sobreexpresa noutros cancros, como o neuroblastoma,<ref name="pmid25563294">{{cite journal |vauthors=Newman EA, Lu F, Bashllari D, Wang L, Opipari AW, Castle VP |title=Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma |journal=Mol. Cancer Res. |volume=13 |issue=3 |pages=470–82 |year=2015 |pmid=25563294 |doi=10.1158/1541-7786.MCR-14-0337 |url=}}</ref> testicular and other germ cell tumors,<ref name="pmid23486608">{{cite journal |vauthors=Mego M, Cierna Z, Svetlovska D, Macak D, Machalekova K, Miskovska V, Chovanec M, Usakova V, Obertova J, Babal P, Mardiak J |title=PARP expression in germ cell tumours |journal=J. Clin. Pathol. |volume=66 |issue=7 |pages=607–12 |year=2013 |pmid=23486608 |doi=10.1136/jclinpath-2012-201088 |url=}}</ref> Ewing’s sarcoma,<ref name="pmid11956622">{{cite journal |vauthors=Newman RE, Soldatenkov VA, Dritschilo A, Notario V |title=Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells |journal=Oncol. Rep. |volume=9 |issue=3 |pages=529–32 |year=2002 |pmid=11956622 |doi= 10.3892/or.9.3.529|url=}}</ref> linfoma maligno,<ref name="pmid1907096">{{cite journal |vauthors=Tomoda T, Kurashige T, Moriki T, Yamamoto H, Fujimoto S, Taniguchi T |title=Enhanced expression of poly(ADP-ribose) synthetase gene in malignant lymphoma |journal=Am. J. Hematol. |volume=37 |issue=4 |pages=223–7 |year=1991 |pmid=1907096 |doi= 10.1002/ajh.2830370402|url=}}</ref> cancro de mama,<ref name="pmid21908496">{{cite journal |vauthors=Rojo F, García-Parra J, Zazo S, Tusquets I, Ferrer-Lozano J, Menendez S, Eroles P, Chamizo C, Servitja S, Ramírez-Merino N, Lobo F, Bellosillo B, Corominas JM, Yelamos J, Serrano S, Lluch A, Rovira A, Albanell J |title=Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer |journal=Ann. Oncol. |volume=23 |issue=5 |pages=1156–64 |year=2012 |pmid=21908496 |doi=10.1093/annonc/mdr361 |url=}}</ref> and colon cancer.<ref name="pmid25526641">{{cite journal |vauthors=Dziaman T, Ludwiczak H, Ciesla JM, Banaszkiewicz Z, Winczura A, Chmielarczyk M, Wisniewska E, Marszalek A, Tudek B, Olinski R |title=PARP-1 expression is increased in colon adenoma and carcinoma and correlates with OGG1 |journal=PLoS ONE |volume=9 |issue=12 |pages=e115558 |year=2014 |pmid=25526641 |pmc=4272268 |doi=10.1371/journal.pone.0115558 |url=}}</ref>