Thornton, Tina M.Delgado, PilarChen, LiangSalas, BeatrizKrementsov, DimitryFernandez, MiriamVernia, SantiagoDavis, Roger J.Heimann, RuthTeuscher, CoryKrangel, Michael S.Ramiro, Almudena RRincon, Mercedes2017-10-302017-10-302016Nat Commun. 2016; 7:105532041-1723http://hdl.handle.net/20.500.12105/5252Variable, diversity and joining (V(D)J) recombination and immunoglobulin class switch recombination (CSR) are key processes in adaptive immune responses that naturally generate DNA double-strand breaks (DSBs) and trigger a DNA repair response. It is unclear whether this response is associated with distinct survival signals that protect T and B cells. Glycogen synthase kinase 3 beta (GSK3 beta) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3 beta on Ser(389) by p38 MAPK (mitogen-activated protein kinase) is induced selectively by DSBs through ATM (ataxia telangiectasia mutated) as a unique mechanism to attenuate the activity of nuclear GSK3 beta and promote survival of cells undergoing DSBs. Inability to inactivate GSK3 beta through Ser(389) phosphorylation in Ser(389)Ala knockin mice causes a decrease in the fitness of cells undergoing V(D)J recombination and CSR. Preselection-Tcrb repertoire is impaired and antigen-specific IgG antibody responses following immunization are blunted in Ser(389)GSK3 beta knockin mice. Thus, GSK3 beta emerges as an important modulator of the adaptive immune response.engVoRhttp://creativecommons.org/licenses/by/4.0/GLYCOGEN-SYNTHASE KINASE-3-BETACLASS SWITCH RECOMBINATIONT-CELL DEVELOPMENTV(D)J RECOMBINATIONDAMAGE RESPONSEHISTONE H2AXP38 MAPKKINASEMCL-1DEATHAtribución 4.0 Internacional26822034710.1038/ncomms10553Nature Communicationsopen access