In vivo reinsertion of excised episomes by the V(D)J recombinase: a potential threat to genomic stability.
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.
Vanura
Katrina
K
Department of Internal Medicine I, Division of Hematology, Medical University of Vienna, Vienna, Austria.
Montpellier
Bertrand
B
Le
Trang
T
Spicuglia
Salvatore
S
Navarro
Jean-Marc
JM
Cabaud
Olivier
O
Roulland
Sandrine
S
Vachez
Elodie
E
Prinz
Immo
I
Ferrier
Pierre
P
Marculescu
Rodrig
R
Jäger
Ulrich
U
Nadel
Bertrand
B
D000818:Animals; D002478:Cells, Cultured; D042822:Genomic Instability; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics; D051379:Mice; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic; D014178:Translocation, Genetic; D045567:VDJ Recombinases / Q000378:metabolism*
D045567:VDJ Recombinases