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Inactivation of nuclear GSK3? by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response.

ABSTRACT: 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 3? (GSK3?) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3? 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? and promote survival of cells undergoing DSBs. Inability to inactivate GSK3? 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-Tcr? repertoire is impaired and antigen-specific IgG antibody responses following immunization are blunted in Ser(389)GSK3? knockin mice. Thus, GSK3? emerges as an important modulator of the adaptive immune response.

SUBMITTER: Thornton TM

PROVIDER: S-EPMC4740185 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Thornton Tina M TM Delgado Pilar P Chen Liang L Salas Beatriz B Krementsov Dimitry D Fernandez Miriam M Vernia Santiago S Davis Roger J RJ Heimann Ruth R Teuscher Cory C Krangel Michael S MS Ramiro Almudena R AR Rincón Mercedes M

Nature communications 20160129

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 Se ...[more]

PMID: 26822034

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Project description:In Saccharomyces cerevisiae, a single double-strand break (DSB) triggers extensive phosphorylation of histone H2A (known as gammaH2AX) over 50 kb on either side of the DSB. This modification is carried out by either of yeastM-^Rs checkpoint kinases, the ATM homolog, Tel1, or the ATR homolog, Mec1. In G1-arrested cells, where there is very little 5M-^R to 3M-^R processing of DSB ends, only Tel1 promotes this modification. We have recently described a second modification gammaH2B - the phosphorylation of the C terminal T129 locus of histone H2B which is also carried out by both Mec1 and Tel1 kinases. To understand in detail how gamma-H2AX and gamma-H2B spread along the chromosome from a DSB we have undertaken a high-density analysis of their occupancy where there is a DSB on three different chromosomes. gamma-H2AX and gamma-H2B modifications are similar, but there is a marked absence of gamma-H2B near telomeres. We find that there is reduced gamma-H2AX and gamma-H2B modification over strongly transcribed regions, even taking into account the reduced histone occupancy of these genes. When transcription of the galactose-regulated genes GAL1, GAL10, GAL7 are turned off by the addition of glucose, gamma-H2AX is restored within 5 min; when these genes are again induced, gamma-H2AX is rapidly lost. Regions more distal to the GAL genes have markedly reduced gamma-H2AX levels that rise rapidly when transcription is repressed, suggesting that transcription acts as a barrier to the propagation of gamma-H2AX away from the DSB. The restoration of gamma-H2AX in transcribed regions can be carried out by either Mec1 or Tel1, even 7 h after break induction, suggesting that Tel1 remains associated with damaged chromosomes for an extended time. In addition, we show that gamma-H2AX can be transferred in trans, to regions unlinked to the DSB that lie in close proximity the DSB. Specifically, if a DSB is generated 14 kb from CEN2, gamma-H2AX is transferred to regions around all the other centromeres, in keeping with observed close proximity of all centromere-adjacent chromosome arms. This transfer can be observed even in the absence of formaldehyde crosslinking of the samples.

Dataset Information

Inactivation of nuclear GSK3? by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response.

Publications

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

Similar Datasets

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