A systematic proteomic study of irradiated DNA repair deficient Nbn-mice.
BACKGROUND
The NBN gene codes for the protein nibrin, which is involved in the detection and repair of DNA double strand breaks (DSBs). The NBN gene is essential in mammals.


RESULTS
We have used a conditional null mutant mouse model in a proteomics approach to identify proteins with modified expression levels after 4 Gy ionizing irradiation in the absence of nibrin in vivo. Altogether, amongst approximately 8,000 resolved proteins, 209 were differentially expressed in homozygous null mutant mice in comparison to control animals. One group of proteins significantly altered in null mutant mice were those involved in oxidative stress and cellular redox homeostasis (p<0.0001). In substantiation of this finding, analysis of Nbn null mutant fibroblasts indicated an increased production of reactive oxygen species following induction of DSBs.


CONCLUSIONS
In humans, biallelic hypomorphic mutations in NBN lead to Nijmegen breakage syndrome (NBS), an autosomal recessive genetic disease characterised by extreme radiosensitivity coupled with growth retardation, immunoinsufficiency and a very high risk of malignancy. This particularly high cancer risk in NBS may be attributable to the compound effect of a DSB repair defect and oxidative stress.
Institut für Humangenetik, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
Anna
A
Melchers
Lars
L
Stöckl
Janina
J
Radszewski
Marco
M
Anders
Harald
H
Krenzlin
Candy
C
Kalischke
Regina
R
Scholz
Andreas
A
Jordan
Grit
G
Nebrich
Joachim
J
Klose
Karl
K
Sperling
Martin
M
Digweed
Ilja
I
Demuth
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins; D015180:Electrophoresis, Gel, Two-Dimensional; D015870:Gene Expression; D018869:Heat-Shock Response; D006706:Homeostasis; D008099:Liver / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020543:Proteome / Q000302:isolation & purification / Q000378:metabolism; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018832:Molecular Chaperones; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D020543:Proteome; D017382:Reactive Oxygen Species; D009243:NAD