Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 369, Issue 3, Pages 835-840Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2008.02.129
Keywords
BRCT tandem domains; DNA repair; double strand break; NBS1; Nijmegen breakage syndrome; R215W mutation; gamma-H2AX
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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.
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