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.

Oxidative DNA damage leading to chromosomal aberrations and mutations

“…In primary Nibrin-deficient mouse fibroblasts, there was increased spontaneous DNA damage relative to wild-type controls, suggestive of inadequate DNA repair. Using the corresponding Nibrin-deficient and wild-type mice, in vivo mutation frequencies were also found to be elevated in the Nibrin-deficient animals (Wessendorf et al, 2014). Furthermore, mutation densities were differentially affected in specific genomic regions in cancer patients depending on their Xeroderma pigmentosum group C (XPC) gene status.…”

Single Nucleotide Polymorphisms of nucleotide excision repair and homologous recombination repair pathways and their role in the risk of osteosarcoma

“…In HRR, nibrin (NBN) is part of the complex involved in recognition of DNA damage, while RAD51 recombinase (RAD51) catalyses homologous search and strand invasion with the help of other proteins, including X-ray complementing defective repair in Chinese hamster cells 3 (XRCC3). 8 , 9 …”