CHK1 and RAD51 activation after DNA damage is regulated via urokinase receptor/TLR4 signaling.
Mechanisms of DNA damage and repair signaling are not completely understood that hinder the efficiency of cancer therapy. Urokinase-type plasminogen activator receptor (PLAUR) is highly expressed in most solid cancers and serves as a marker of poor prognosis. We show that PLAUR actively promotes DNA repair in cancer cells. On the contrary, downregulation of PLAUR expression results in delayed DNA repair. We found PLAUR to be essential for activation of Checkpoint kinase 1 (CHK1); maintenance of cell cycle arrest after DNA damage in a TP53-dependent manner; expression, nuclear import and recruitment to DNA-damage foci of RAD51 recombinase, the principal protein involved in the homologous recombination repair pathway. Underlying mechanism implies auto-/paracrine signaling of PLAUR/TLR4 receptor complex leading to activation of CHK1 and DNA repair. The signaling is induced by a danger molecule released by DNA-damaged cells and mediates, at least partially, activation of DNA-damage response. This study describes a new mechanism of DNA repair activation initiated by auto-/paracrine signaling of membrane receptors PLAUR/TLR4. It adds to the understanding of role of PLAUR in cancer and provides a rationale for therapeutic targeting of PLAUR/TLR4 interaction in TP53-positive cancers.
Department of Nephrology, Hannover Medical School, Hannover D-30625, Germany.
Pavan B
PB
Narayanaswamy
Department of Nephrology, Hannover Medical School, Hannover D-30625, Germany.
Sergey
S
Tkachuk
Department of Nephrology, Hannover Medical School, Hannover D-30625, Germany.
Hermann
H
Haller
Department of Nephrology, Hannover Medical School, Hannover D-30625, Germany.
Inna
I
Dumler
Department of Nephrology, Hannover Medical School, Hannover D-30625, Germany.
Yulia
Y
Kiyan
D059447:Cell Cycle Checkpoints; D002467:Cell Nucleus / Q000378:metabolism; D000071877:Checkpoint Kinase 1 / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D051197:Toll-Like Receptor 4; D016159:Tumor Suppressor Protein p53; D000071877:Checkpoint Kinase 1; D051135:Rad51 Recombinase
Nat Cell Biol. 2005 Feb;7(2):195-201
15665856
J Biol Chem. 2009 Feb 13;284(7):4132-9
19060337
Hepatology. 2013 May;57(5):1869-81
23299825
Nat Med. 2007 Sep;13(9):1050-9
17704786
Br J Clin Pharmacol. 2013 Sep;76(3):358-69
23593991
J Vis Exp. 2010 Sep 08;(43):null
20864925
Theranostics. 2013 Jun 25;3(7):487-95
23843896
PLoS Genet. 2011 Mar;7(3):e1001360
21483755
J Mol Cell Cardiol. 2014 Jan;66:72-82
24239845
J Vasc Res. 2013;50(2):109-23
23172421
Dev Cell. 2010 Apr 20;18(4):533-43
20412769
Blood. 2014 Jan 16;123(3):377-90
24277079
PLoS One. 2014 Jul 02;9(7):e101529
24987841
Blood. 2011 Jul 28;118(4):1062-8
21653319
J Cancer Res Ther. 2014 Oct-Dec;10(4):819-33
25579514
Methods Mol Biol. 2005;296:157-66
15576930
FEBS Lett. 2010 May 3;584(9):1923-30
20036661
DNA Repair (Amst). 2008 May 3;7(5):686-93
18243065
Nat Rev Cancer. 2016 Jan;16(1):20-33
26678314
Front Pharmacol. 2015 Jul 27;6:154
26283964
Oncogene. 2006 Nov 23;25(55):7305-10
16785993
Int J Mol Sci. 2015 Jan 23;16(2):2591-609
25625514
Cell Struct Funct. 2015 ;40(1):43-50
25748360
Autophagy. 2013 Jun 1;9(6):925-7
23518600
Cancer Res. 2015 Jun 15;75(12):2405-10
25998620
Cancer Res. 2010 Jun 15;70(12 ):4972-81
20501833
Int J Cancer. 2014 Mar 1;134(5):1013-23
23613359
Mediators Inflamm. 2015;2015:146282
26491220
Hum Mutat. 2002 Jun;19(6):607-14
12007217
Nat Rev Immunol. 2013 Jun;13(6):453-60
23681101
Biochem Cell Biol. 2016 Oct;94(5):407-418
27224545
Pharmacol Ther. 2014 Apr;142(1):1-10
24140082
Br J Cancer. 2014 Sep 23;111(7):1319-26
25003660
Mol Syst Biol. 2010 Jun 8;6:371
20531401
Anticancer Agents Med Chem. 2012 Jul;12(6):631-9
22263797
Methods Mol Biol. 2012;920:613-26
22941631
Atherosclerosis. 2007 Dec;195(2):254-61
17275828
Oncotarget. 2014 May 30;5(10):3115-29
24833108