Journal Article

Impact of heterozygous c.657-661del, p.I171V and p.R215W mutations in <i>NBN</i> on nibrin functions

Agnieszka Dzikiewicz-Krawczyk, Maria Mosor, Danuta Januszkiewicz and Jerzy Nowak

in Mutagenesis

Published on behalf of United Kingdom Environmental Mutagen Society

Volume 27, issue 3, pages 337-343
Published in print May 2012 | ISSN: 0267-8357
Published online November 2011 | e-ISSN: 1464-3804 | DOI: https://dx.doi.org/10.1093/mutage/ger084
Impact of heterozygous c.657-661del, p.I171V and p.R215W mutations in NBN on nibrin functions

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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.

Journal Article.  4825 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics ; Genetics and Genomics

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