Deficiency of the DNA repair protein nibrin increases the basal but not the radiation induced mutation frequency in vivo

Petra Wessendorf, Jan Vijg, André Nussenzweig, Martin Digweed

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)11-16
Number of pages6
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume769
DOIs
StatePublished - 2014

Fingerprint

DNA Repair-Deficiency Disorders
Mutation Rate
Radiation
Mutation
Proteins
Double-Stranded DNA Breaks
Radiation Tolerance
DNA Damage
Lymphatic System
Lymphoid Tissue
DNA Replication
DNA Repair
Cell Cycle
Plasmids
Fibroblasts
Apoptosis

Keywords

  • DNA damage
  • Haploinsufficiency
  • Mismatch repair

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis
  • Medicine(all)

Cite this

Deficiency of the DNA repair protein nibrin increases the basal but not the radiation induced mutation frequency in vivo. / Wessendorf, Petra; Vijg, Jan; Nussenzweig, André; Digweed, Martin.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 769, 2014, p. 11-16.

Research output: Contribution to journalArticle

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AU - Nussenzweig, André

AU - Digweed, Martin

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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.

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