Nijmegen breakage syndrome (NBS) is a genetic disorder characterized by chromosomal instability and hypersensitivity to ionising radiation. Compound heterozygous 657del5/R215W NBS patients display a clinical phenotype more severe than the majority of NBS patients homozygous for the 657del5 mutation. The NBS1 protein, mutated in NBS patients, contains a FHA/BRCT domain necessary for the DNA-double strand break (DSB) damage response. Recently, a second BRCT domain has been identified, however, its role is still unknown. Here, we demonstrate that the R215W mutation in NBS1 impairs histone gamma-H2AX binding after induction of DNA damage, leading to a delay in DNA-DSB rejoining. Molecular modelling reveals that the 215 residue of NBS1 is located between the two BRCT domains, affecting their relative orientation that appears critical for gamma-H2AX binding. Present data represent the first evidence for the role of NBS1 tandem BRCT domains in gamma-H2AX recognition, and could explain the severe phenotype observed in 657del5/R215W NBS patients. (c) 2008 Elsevier Inc. All rights reserved.
di Masi A, Viganotti M, Polticelli F, Ascenzi P, Tanzarella C, & Antoccia A (2008). The R215W mutation in NBS1 impairs gamma-H2AX binding and affects DNA repair: molecular bases for the severe phenotype of 657del5/R215W Nijmegen breakage syndrome patients RID A-4573-2009. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 369(3), 835-840 [10.1016/j.bbrc.2008.02.129 WC Biochemistry & Molecular Biology; Biophysics].
Titolo: | The R215W mutation in NBS1 impairs gamma-H2AX binding and affects DNA repair: molecular bases for the severe phenotype of 657del5/R215W Nijmegen breakage syndrome patients RID A-4573-2009 | |
Autori: | ||
Data di pubblicazione: | 2008 | |
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Citazione: | di Masi A, Viganotti M, Polticelli F, Ascenzi P, Tanzarella C, & Antoccia A (2008). The R215W mutation in NBS1 impairs gamma-H2AX binding and affects DNA repair: molecular bases for the severe phenotype of 657del5/R215W Nijmegen breakage syndrome patients RID A-4573-2009. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 369(3), 835-840 [10.1016/j.bbrc.2008.02.129 WC Biochemistry & Molecular Biology; Biophysics]. | |
Abstract: | Nijmegen breakage syndrome (NBS) is a genetic disorder characterized by chromosomal instability and hypersensitivity to ionising radiation. Compound heterozygous 657del5/R215W NBS patients display a clinical phenotype more severe than the majority of NBS patients homozygous for the 657del5 mutation. The NBS1 protein, mutated in NBS patients, contains a FHA/BRCT domain necessary for the DNA-double strand break (DSB) damage response. Recently, a second BRCT domain has been identified, however, its role is still unknown. Here, we demonstrate that the R215W mutation in NBS1 impairs histone gamma-H2AX binding after induction of DNA damage, leading to a delay in DNA-DSB rejoining. Molecular modelling reveals that the 215 residue of NBS1 is located between the two BRCT domains, affecting their relative orientation that appears critical for gamma-H2AX binding. Present data represent the first evidence for the role of NBS1 tandem BRCT domains in gamma-H2AX recognition, and could explain the severe phenotype observed in 657del5/R215W NBS patients. (c) 2008 Elsevier Inc. All rights reserved. | |
Handle: | http://hdl.handle.net/11590/153648 | |
Appare nelle tipologie: | 1.1 Articolo in rivista |