Detection of a tandem BRCT in Nbs1 and Xrs2 with functional implications in the DNA damage response.
BACKGROUND
Human Nbs1 and its homolog Xrs2 in Saccharomyces cerevisiae are part of the conserved MRN complex (MRX in yeast) which plays a crucial role in maintaining genomic stability. NBS1 corresponds to the gene mutated in the Nijmegen breakage syndrome (NBS) known as a radiation hyper-sensitive disease. Despite the conservation and the importance of the MRN complex, the high sequence divergence between Nbs1 and Xrs2 precluded the identification of common domains downstream of the N-terminal Fork-Head Associated (FHA) domain.


RESULTS
Using HMM-HMM profile comparisons and structure modelling, we assessed the existence of a tandem BRCT in both Nbs1 and Xrs2 after the FHA. The structure-based conservation analysis of the tandem BRCT in Nbs1 supports its function as a phosphoserine binding domain. Remarkably, the 5 bp deletion observed in 95% of NBS patients cleaves the tandem at the linker region while preserving the structural integrity of each BRCT domain in the resulting truncated gene products.
Becker
Emmanuelle
E
Service de Biophysique des Fonctions Membranaires, URA CNRS 2096, Département de Biologie Joliot-Curie, CEA Saclay, 91191 Gif-Sur-Yvette Cedex, France.
Meyer
Vincent
V
Madaoui
Hocine
H
Guerois
Raphaël
R
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D019295:Computational Biology / Q000379:methods*; D004249:DNA Damage; D004260:DNA Repair; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012091:Repetitive Sequences, Nucleic Acid; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C086929:XRS2 protein, S cerevisiae