In vivo reinsertion of excised episomes by the V(D)J recombinase: a potential threat to genomic stability.

Katrina Vanura (1) , Bertrand Montpellier (2) , Trang Le (1) , Salvatore Spicuglia (2) , Jean-Marc Navarro (2) , Olivier Cabaud (2) , Sandrine Roulland (2) , Elodie Vachez (2) , Immo Prinz (2) , Pierre Ferrier (2) , Rodrig Marculescu (1) , Ulrich Jäger (1) , Bertrand Nadel (2)

1 Division of Hematology
2 CIML - Centre d'Immunologie de Marseille - Luminy

It has long been thought that signal joints, the byproducts of V(D)J recombination, are not involved in the dynamics of the rearrangement process. Evidence has now started to accumulate that this is not the case, and that signal joints play unsuspected roles in events that might compromise genomic integrity. Here we show both ex vivo and in vivo that the episomal circles excised during the normal process of receptor gene rearrangement may be reintegrated into the genome through trans-V(D)J recombination occurring between the episomal signal joint and an immunoglobulin/T-cell receptor target. We further demonstrate that cryptic recombination sites involved in T-cell acute lymphoblastic leukemia-associated chromosomal translocations constitute hotspots of insertion. Eventually, the identification of two in vivo cases associating episomal reintegration and chromosomal translocation suggests that reintegration events are linked to genomic instability. Altogether, our data suggest that V(D)J-mediated reintegration of episomal circles, an event likely eluding classical cytogenetic screenings, might represent an additional potent source of genomic instability and lymphoid cancer.

Domaines: Immunologie

Katrina Vanura, Bertrand Montpellier, Trang Le, Salvatore Spicuglia, Jean-Marc Navarro, et al.. In vivo reinsertion of excised episomes by the V(D)J recombinase: a potential threat to genomic stability.. PLoS Biology, 2007, 5 (3), pp.e43. ⟨10.1371/journal.pbio.0050043⟩. ⟨hal-00165464⟩