Cernunnos, a Novel Nonhomologous End-Joining Factor, Is Mutated in Human Immunodeficiency with Microcephaly

DNA double-strand breaks (DSBs) occur at random upon genotoxic stresses and represent obligatory intermediates during physiological DNA rearrangement events such as the V(D)J recombination in the immune system. DSBs, which are among the most toxic DNA lesions, are preferentially repaired by the nonh...

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Bibliographic Details
Published in:Cell 2006-01, Vol.124 (2), p.287-299
Main Authors: Buck, Dietke, Malivert, Laurent, de Chasseval, Régina, Barraud, Anne, Fondanèche, Marie-Claude, Sanal, Ozden, Plebani, Alessandro, Stéphan, Jean-Louis, Hufnagel, Markus, le Deist, Françoise, Fischer, Alain, Durandy, Anne, de Villartay, Jean-Pierre, Revy, Patrick
Format: Article
Language:English
Subjects:
Adolescent
B-Lymphocytes - immunology
Base Sequence
Cell Cycle - radiation effects
Child
Child, Preschool
DNA Repair Enzymes
DNA Repair-Deficiency Disorders - complications
DNA Repair-Deficiency Disorders - genetics
DNA Repair-Deficiency Disorders - immunology
DNA, Complementary - metabolism
DNA-Binding Proteins - genetics
Fibroblasts - immunology
Fibroblasts - radiation effects
Gene Rearrangement, B-Lymphocyte
Growth Disorders - complications
Growth Disorders - genetics
Growth Disorders - immunology
Humans
Immunoglobulin Joining Region - genetics
Immunoglobulin Variable Region - genetics
Lymphopenia - complications
Lymphopenia - genetics
Lymphopenia - immunology
Microcephaly - complications
Microcephaly - genetics
Microcephaly - immunology
Molecular Sequence Data
Mutation
Radiation Tolerance - genetics
Syndrome
T-Lymphocytes - immunology
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Summary:DNA double-strand breaks (DSBs) occur at random upon genotoxic stresses and represent obligatory intermediates during physiological DNA rearrangement events such as the V(D)J recombination in the immune system. DSBs, which are among the most toxic DNA lesions, are preferentially repaired by the nonhomologous end-joining (NHEJ) pathway in higher eukaryotes. Failure to properly repair DSBs results in genetic instability, developmental delay, and various forms of immunodeficiency. Here we describe five patients with growth retardation, microcephaly, and immunodeficiency characterized by a profound T+B lymphocytopenia. An increased cellular sensitivity to ionizing radiation, a defective V(D)J recombination, and an impaired DNA-end ligation process both in vivo and in vitro are indicative of a general DNA repair defect in these patients. All five patients carry mutations in the Cernunnos gene, which was identified through cDNA functional complementation cloning. Cernunnos/XLF represents a novel DNA repair factor essential for the NHEJ pathway.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2005.12.030