title: Deficiency of the DNA repair protein nibrin increases the basal but not the radiation induced mutation frequency in vivo.
abstract: 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.
authors.affiliation: Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Wessendorf
authors.affiliation: Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institute of Health, 37 Convent Drive, Room 1106, Bethesda, MD 20892, USA.
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
authors.affiliation: Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. Electronic address: martin.digweed@charite.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Digweed
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics*; D002478:Cells, Cultured; D019457:Chromosome Breakage / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins; D005720:Gamma Rays / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D059645:Mutation Rate; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins
keywords: DNA damage; Haploinsufficiency; Mismatch repair