Oncotarget

Research Papers:

A new phosphorylated form of Ku70 identified in resistant leukemic cells confers fast but unfaithful DNA repair in cancer cell lines

Julien Bouley _, Lina Saad, Romain Grall, Amelie Schellenbauer, Denis Biard, Vincent Paget, Sandrine Morel-Altmeyer, Olivier Guipaud, Christophe Chambon, Bernard Salles, Karim Maloum, Hélène Merle-Béral, Sylvie Chevillard and Jozo Delic

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Oncotarget. 2015; 6:27980-28000. https://doi.org/10.18632/oncotarget.4735

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Abstract

Julien Bouley1,7,*, Lina Saad1,*, Romain Grall1,*, Amelie Schellenbauer1, Denis Biard2, Vincent Paget1, Sandrine Morel-Altmeyer1, Olivier Guipaud1,8, Christophe Chambon3, Bernard Salles4, Karim Maloum5, Hélène Merle-Béral5,6, Sylvie Chevillard1, Jozo Delic1

1Laboratoire de Cancérologie Expérimentale, Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l’Energie Atomique et aux Energies Renouvelables (CEA), 92265 Fontenay aux Roses, France

2Institut de Maladies Emergentes et des Thérapies Innovantes (iMETI), Service d’Étude des Prions et des Infections Atypiques (SEPIA), CEA, 92265 Fontenay aux Roses, France

3Service de Spectrométrie de Masse, INRA Theix, 63122 St Genès Champanelle, France

4UMR 1331 TOXALIM, INRA/INP/UPS, F-31027 Toulouse, France

5Service d’Hématologie Biologique, Hôpital Pitié-Salpêtrière, 75000 Paris, France

6Université Pierre et Marie Curie, Paris VI, INSERM, UMR-S 872, Programmed Cell Death and Physiopathology of Tumor Cells, Centre de Recherche des Cordeliers 75000 Paris, France

7Laboratoire de Spectrométrie de Masse, Stallergens, 92160 Antony, France

8Laboratoire de Radiopathologie et de Thérapies Expérimentales, Institut de Radioprotection et de Sureté Nucléaire (IRSN), 92265 Fontenay aux Roses, France

*These authors have contributed equally to this work

Correspondence to:

Jozo Delic, e-mail: jozo.delic@cea.fr

Keywords: phospho-Ku70, c-NHEJ, DNA repair kinetic, CLL, gamma-H2AX/ATM/DNA-PKcs

Received: February 10, 2015     Accepted: August 03, 2015     Published: August 13, 2015

ABSTRACT

Ku70-dependent canonical nonhomologous end-joining (c-NHEJ) DNA repair system is fundamental to the genome maintenance and B-cell lineage. c-NHEJ is upregulated and error-prone in incurable forms of chronic lymphocytic leukemia which also displays telomere dysfunction, multiple chromosomal aberrations and the resistance to DNA damage-induced apoptosis. We identify in these cells a novel DNA damage inducible form of phospho-Ku70. In vitro in different cancer cell lines, Ku70 phosphorylation occurs in a heterodimer Ku70/Ku80 complex within minutes of genotoxic stress, necessitating its interaction with DNA damage-induced kinase pS2056-DNA-PKcs and/or pS1981-ATM. The mutagenic effects of phospho-Ku70 are documented by a defective S/G2 checkpoint, accelerated disappearance of γ-H2AX foci and kinetics of DNA repair resulting in an increased level of genotoxic stress-induced chromosomal aberrations. Together, these data unveil an involvement of phospho-Ku70 in fast but inaccurate DNA repair; a new paradigm linked to both the deregulation of c-NHEJ and the resistance of malignant cells.


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