DEK is required for homologous recombination repair of DNA breaks.
DEK is a highly conserved chromatin-bound protein whose upregulation across cancer types correlates with genotoxic therapy resistance. Loss of DEK induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair. While these DEK-deficiency phenotypes were thought to arise from a moderate attenuation of non-homologous end joining (NHEJ) repair, the role of DEK in DNA repair remains incompletely understood. We present new evidence demonstrating the observed decrease in NHEJ is insufficient to impact immunoglobulin class switching in DEK knockout mice. Furthermore, DEK knockout cells were sensitive to apoptosis with NHEJ inhibition. Thus, we hypothesized DEK plays additional roles in homologous recombination (HR). Using episomal and integrated reporters, we demonstrate that HR repair of conventional DSBs is severely compromised in DEK-deficient cells. To define responsible mechanisms, we tested the role of DEK in the HR repair cascade. DEK-deficient cells were impaired for γH2AX phosphorylation and attenuated for RAD51 filament formation. Additionally, DEK formed a complex with RAD51, but not BRCA1, suggesting a potential role regarding RAD51 filament formation, stability, or function. These findings define DEK as an important and multifunctional mediator of HR, and establish a synthetic lethal relationship between DEK loss and NHEJ inhibition.
Division of Oncology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Eric A
EA
Smith
Department of Obstetrics and Gynecology; Ulm University, Ulm, 89075, Germany.
Boris
B
Gole
Department of Medicine, Division of Hematology-Oncology and Cancer Research Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
Nicholas A
NA
Willis
Chromatin Structure and Function Group, The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, 2200, Denmark.
Rebeca
R
Soria
Chromatin Structure and Function Group, The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, 2200, Denmark.
Linda M
LM
Starnes
Division of Oncology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Eric F
EF
Krumpelbeck
Division of Oncology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Anil G
AG
Jegga
Division of Experimental Hematology and Cancer Biology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Abdullah M
AM
Ali
Institute of Biochemistry and Molecular Biology; Medical School, RWTH Aachen University, Aachen, 52074, Germany.
Haihong
H
Guo
Division of Experimental Hematology and Cancer Biology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Amom R
AR
Meetei
Division of Experimental Hematology and Cancer Biology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Paul R
PR
Andreassen
Institute of Biochemistry and Molecular Biology; Medical School, RWTH Aachen University, Aachen, 52074, Germany.
Ferdinand
F
Kappes
Division of Oncology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Lisa M Privette
LM
Vinnedge
Chromatin Structure and Function Group, The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, 2200, Denmark.
Jeremy A
JA
Daniel
Department of Medicine, Division of Hematology-Oncology and Cancer Research Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
Ralph
R
Scully
Department of Obstetrics and Gynecology; Ulm University, Ulm, 89075, Germany.
Lisa
L
Wiesmüller
Division of Oncology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Susanne I
SI
Wells
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000378:metabolism; D011839:Radiation, Ionizing; D051716:Replication Protein A / Q000378:metabolism
D002868:Chromosomal Proteins, Non-Histone; C519564:DEK protein, mouse; D004268:DNA-Binding Proteins; C084738:DEK protein, human; D006657:Histones; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D047428:Protein Kinase Inhibitors; D051716:Replication Protein A; C475961:gamma-H2AX protein, mouse; D051135:Rad51 Recombinase