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Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response.

Publication ,  Journal Article
Thornton, TM; Delgado, P; Chen, L; Salas, B; Krementsov, D; Fernandez, M; Vernia, S; Davis, RJ; Heimann, R; Teuscher, C; Krangel, MS ...
Published in: Nat Commun
January 29, 2016

Variable, 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 3β (GSK3β) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3β 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 GSK3β and promote survival of cells undergoing DSBs. Inability to inactivate GSK3β 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-Tcrβ repertoire is impaired and antigen-specific IgG antibody responses following immunization are blunted in Ser(389)GSK3β knockin mice. Thus, GSK3β emerges as an important modulator of the adaptive immune response.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

January 29, 2016

Volume

7

Start / End Page

10553

Location

England

Related Subject Headings

  • Phosphorylation
  • Mutation
  • Mice
  • Lymphocytes
  • Humans
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Gene Knock-In Techniques
  • Gene Expression Regulation, Enzymologic
  • DNA Repair
 

Citation

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Thornton, T. M., Delgado, P., Chen, L., Salas, B., Krementsov, D., Fernandez, M., … Rincón, M. (2016). Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response. Nat Commun, 7, 10553. https://doi.org/10.1038/ncomms10553
Thornton, Tina M., Pilar Delgado, Liang Chen, Beatriz Salas, Dimitry Krementsov, Miriam Fernandez, Santiago Vernia, et al. “Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response.Nat Commun 7 (January 29, 2016): 10553. https://doi.org/10.1038/ncomms10553.
Thornton TM, Delgado P, Chen L, Salas B, Krementsov D, Fernandez M, et al. Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response. Nat Commun. 2016 Jan 29;7:10553.
Thornton, Tina M., et al. “Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response.Nat Commun, vol. 7, Jan. 2016, p. 10553. Pubmed, doi:10.1038/ncomms10553.
Thornton TM, Delgado P, Chen L, Salas B, Krementsov D, Fernandez M, Vernia S, Davis RJ, Heimann R, Teuscher C, Krangel MS, Ramiro AR, Rincón M. Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response. Nat Commun. 2016 Jan 29;7:10553.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

January 29, 2016

Volume

7

Start / End Page

10553

Location

England

Related Subject Headings

  • Phosphorylation
  • Mutation
  • Mice
  • Lymphocytes
  • Humans
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Gene Knock-In Techniques
  • Gene Expression Regulation, Enzymologic
  • DNA Repair