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The Mechanism of Chromosome 7 Inversion in Human Lymphocytes Expressing Chimeric ß TCR¹

Christelle Retière^*, Franck Halary^*, Marie-Alix Peyrat^*, Françoise Le Deist, Marc Bonneville^* and Marie-Martine Hallet^2,*

^* Institut National de la Santé et de la Recherche Médicale U463, Institut de Biologie, Nantes, France; and Institut National de la Santé et de la Recherche Médicale U132, Hopital Necker, Enfants Malades, Paris, France

Functional chimeric TCR chains, encoded by VJCß or VJßCß hybrid gene TCR, are expressed at the surface of a small fraction of ß T lymphocytes in healthy individuals. Their frequency is dramatically increased in patients with ataxia-telangiectasia, a syndrome associated with inherited genomic instability. As the TCR and ß loci are in an inverted orientation on chromosome 7, the generation of such hybrid genes requires at least an inversion event. Until now, neither the sequences involved in this genetic mechanism nor the number of recombinations leading to the formation of functional transcriptional units have been characterized. In this manuscript, we demonstrate that at least two rearrangements, involving classical recombination signal sequence and the V(D)J recombinase complex, lead to the formation of productive hybrid genes. A primary inversion 7 event between Dß and J genic segments generates CVß and CßV hybrid loci. Within the CVß locus, secondary rearrangements between V and J or V and Jß elements generate functional genes. Besides, our results suggest that secondary rearrangements were blocked in the CßV locus of normal but not ataxia-telangiectasia T lymphocytes. We also provide formal evidence that the same Dß-3' recombination signal sequence can be used in successive rearrangements with J and Jß genic segments, thus showing that a signal joint has been involved in a secondary recombination event.

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