title: V(D)J rearrangement in Nijmegen breakage syndrome.
abstract: Repair of DNA double-strand breaks is essential for maintenance of genomic stability, and is specifically required for rearrangement of immunoglobulin (Ig) and T cell receptor (TCR) loci during development of the immune system. Abnormalities in these repair processes also contribute to oncogenic chromosomal rearrangements that underlie many lymphoid malignancies. Nijmegen breakage syndrome (NBS) is a rare autosomal recessive condition characterized by immunodeficiency, radiation sensitivity, and increased predisposition to lymphoid cancers bearing oncogenic Ig and TCR locus translocations. NBS patients fail to produce nibrin, a protein required for the nuclear localization and function of a DNA repair complex that includes Mre11 and Rad50. Mre11 has biochemical properties that suggest a potential role in V(D)J recombination. We studied V(D)J recombination in NBS cells in vitro and in vivo, using cell lines and peripheral blood leukocyte DNA from NBS patients. We found that NBS cells were competent to rejoin signal substrates with normal efficiency and high fidelity. Coding substrates were similarly rejoined efficiently, and coding end structures appeared normal. In B cells from NBS patients, the spectrums of IgH CDR3 regions were diverse and normally distributed. Moreover, the lengths and composition of Igkappa VJ joins and IgH VDJ joins derived from NBS and normal subjects were indistinguishable. Our data indicate that nibrin plays no essential role in V(D)J recombination and is not required for the generation of an apparently diverse B cell repertoire.
authors.affiliation: Molecular Genetics Program, Virginia Mason Research Center, 1201 Ninth Avenue, Seattle, WA 98101-2795, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Yeo
authors.forename: D
authors.initials: D
authors.lastname: Xia
authors.forename: S
authors.initials: S
authors.lastname: Hassouneh
authors.forename: X O
authors.initials: XO
authors.lastname: Yang
authors.forename: D E
authors.initials: DE
authors.lastname: Sabath
authors.forename: K
authors.initials: K
authors.lastname: Sperling
authors.forename: R A
authors.initials: RA
authors.lastname: Gatti
authors.forename: P
authors.initials: P
authors.lastname: Concannon
authors.forename: D M
authors.initials: DM
authors.lastname: Willerford
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D019457:Chromosome Breakage / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins; D011995:Recombination, Genetic / Q000235:genetics*; D013577:Syndrome
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D000076228:MRE11 Homologue Protein