Positional cloning and functional analysis of the gene responsible for Nijmegen breakage syndrome, NBS1.
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, combined immunodeficiency, and a high incidence of lymphoid tumor. Cells from NBS patients show chromosomal instability, hypersensitivity to ionizing radiation and abnormal p53-mediated cell cycle regulation. We cloned the underlying gene for NBS, designated NBS1, by complementation-assisted positional cloning from the candidate region 8q21. Large genomic sequencing, as well as a search using computer programs, provides a powerful approach for identifying the underlying gene for a disease. The NBS1 gene encodes a protein of 754 amino acids that has FHA and BRCT domains which often are conserved in cell-cycle checkpoint proteins. The gene has weak homology to the yeast (Saccharomyces cerevisiae) Xrs2 protein in the N-terminus region. Like yeast Xrs2, the NBS1 protein forms a complex with hRAD50/hMRE11, and the complex is condensed as foci in the nucleus after irradiation, indicative that this triple-complex is a crucial factor in DNA repair. Functional analysis of the NBS1 protein is in progress and it should provide further clues to understanding the repair mechanism of radiation-induced DNA double-strand breaks.
Tauchi
H
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Department of Radiation Biology, Hiroshima University, Japan. htauchi@hiroshima-u.ac.jp
D000595:Amino Acid Sequence; D001260:Ataxia Telangiectasia / Q000145:classification / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000737:chemistry; D002461:Cell Line, Transformed; D002877:Chromosomes, Human / Q000528:radiation effects / Q000648:ultrastructure; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D003001:Cloning, Molecular; D004260:DNA Repair / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics; D005808:Genes, Recessive; D005816:Genetic Complementation Test; D006801:Humans; D008831:Microcephaly / Q000235:genetics*; D008969:Molecular Sequence Data; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D011044:Poland / Q000453:epidemiology; D017434:Protein Structure, Tertiary; D011836:Radiation Tolerance / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D013577:Syndrome
D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C086929:XRS2 protein, S cerevisiae