title: Impact of heterozygous c.657-661del, p.I171V and p.R215W mutations in NBN on nibrin functions.
abstract: Nibrin, product of the NBN gene, together with MRE11 and RAD50 is involved in DNA double-strand breaks (DSBs) sensing and repair, induction of apoptosis and cell cycle control. Biallelic NBN mutations cause the Nijmegen breakage syndrome, a chromosomal instability disorder characterised by, among other things, radiosensitivity, immunodeficiency and an increased cancer risk. Several studies have shown an association of heterozygous c.657-661del, p.I171V and p.R215W mutations in the NBN gene with a variety of malignancies but the data are controversial. Little is known, however, whether and to what extent do these mutations in heterozygous state affect nibrin functions. We examined frequency of chromatid breaks, DSB repair, defects in S-phase checkpoint and radiosensitivity in X-ray-irradiated cells from control individuals, NBS patients and heterozygous carriers of the c.657-661del, p.I171V and p.R215W mutations. While cells homozygous for c.657-661del displayed a significantly increased number of chromatid breaks and residual γ-H2AX foci, as well as abrogation of the intra-S-phase checkpoint following irradiation, which resulted in increased radiosensitivity, cells with heterozygous c.657-661del, p.I171V and p.R215W mutations behaved similarly to control cells. Significant differences in the frequency of spontaneous and ionising radiation-induced chromatid breaks and the level of persistent γ-H2AX foci were observed when comparing control and mutant cells heterozygous for c.657-661del. However, it is still possible that heterozygous NBN mutations may contribute to cancer development.
authors: Department of Molecular Pathology, Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland. krawczyk@man.poznan.pl
authors: Agnieszka
authors: A
authors: Dzikiewicz-Krawczyk
authors: Maria
authors: M
authors: Mosor
authors: Danuta
authors: D
authors: Januszkiewicz
authors: Jerzy
authors: J
authors: Nowak
mesh_terms: D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D042622:DNA Repeat Expansion; D006579:Heterozygote; D006657:Histones / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D049932:Nijmegen Breakage Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D059807:S Phase Cell Cycle Checkpoints / Q000528:radiation effects; D017384:Sequence Deletion
chemical_list: D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; C112156:NBN protein, human; D009687:Nuclear Proteins; D004247:DNA