TY - JOUR
T1 - Deficiency of the DNA repair protein nibrin increases the basal but not the radiation induced mutation frequency in vivo
AU - Wessendorf, Petra
AU - Vijg, Jan
AU - Nussenzweig, André
AU - Digweed, Martin
N1 - Funding Information:
The authors are grateful to Bettina Ueberle, Klinik fuer Dermatologie und Allergologie, Universitaetsklinikum Ulm, for instruction in the lacZ assay and Brigitte Köttgen, Institut für Klinische Chemie und Pathochemie, Charité Berlin for instruction in the comet assay. We thank Susanne Rothe for mouse genotyping, Vittoria von Petersdorff for assistance in DNA sequencing and Moonsook Lee for assistance with the lacZ assay. This work was supported by the Deutsche Forschungsgemeinschaft (grant number DI 505/3-1 to M.D.) and NIH to J.V.
PY - 2014/11
Y1 - 2014/11
N2 - Nibrin (NBN) is a member of a DNA repair complex together with MRE11 and RAD50. The complex is associated particularly with the repair of DNA double strand breaks and with the regulation of cell cycle check points. Hypomorphic mutation of components of the complex leads to human disorders characterised by radiosensitivity and increased tumour occurrence, particularly of the lymphatic system. We have examined here the relationship between DNA damage, mutation frequency and mutation spectrum in vitro and in vivo in mouse models carrying NBN mutations and a lacZ reporter plasmid. We find that NBN mutation leads to increased spontaneous DNA damage in fibroblasts in vitro and high basal mutation rates in lymphatic tissue of mice in vivo. The characteristic mutation spectrum is dominated by single base transitions rather than the deletions and complex rearrangements expected after abortive repair of DNA double strand breaks. We conclude that in the absence of wild type nibrin, the repair of spontaneous errors, presumably arising during DNA replication, makes a major contribution to the basal mutation rate. This applies also to cells heterozygous for an NBN null mutation. Mutation frequencies after irradiation in vivo were not increased in mice with nibrin mutations as might have been expected considering the radiosensitivity of NBS patient cells in vitro. Evidently apoptosis is efficient, even in the absence of wild type nibrin.
AB - Nibrin (NBN) is a member of a DNA repair complex together with MRE11 and RAD50. The complex is associated particularly with the repair of DNA double strand breaks and with the regulation of cell cycle check points. Hypomorphic mutation of components of the complex leads to human disorders characterised by radiosensitivity and increased tumour occurrence, particularly of the lymphatic system. We have examined here the relationship between DNA damage, mutation frequency and mutation spectrum in vitro and in vivo in mouse models carrying NBN mutations and a lacZ reporter plasmid. We find that NBN mutation leads to increased spontaneous DNA damage in fibroblasts in vitro and high basal mutation rates in lymphatic tissue of mice in vivo. The characteristic mutation spectrum is dominated by single base transitions rather than the deletions and complex rearrangements expected after abortive repair of DNA double strand breaks. We conclude that in the absence of wild type nibrin, the repair of spontaneous errors, presumably arising during DNA replication, makes a major contribution to the basal mutation rate. This applies also to cells heterozygous for an NBN null mutation. Mutation frequencies after irradiation in vivo were not increased in mice with nibrin mutations as might have been expected considering the radiosensitivity of NBS patient cells in vitro. Evidently apoptosis is efficient, even in the absence of wild type nibrin.
KW - DNA damage
KW - Haploinsufficiency
KW - Mismatch repair
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U2 - 10.1016/j.mrfmmm.2014.07.001
DO - 10.1016/j.mrfmmm.2014.07.001
M3 - Article
C2 - 25771721
AN - SCOPUS:84904726192
SN - 0027-5107
VL - 769
SP - 11
EP - 16
JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
ER -