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DYRK1A regulates B cell class switch recombination through phosphorylation of MSH6

ABSTRACT: DYRK1A regulates B cell class switch recombination through phosphorylation of MSH6

PROVIDER: PRJNA849420 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19660800.fastq.gz	Fastqsanger.gz
	SRR19660801.fastq.gz	Fastqsanger.gz
	SRR19660802.fastq.gz	Fastqsanger.gz
	SRR19660803.fastq.gz	Fastqsanger.gz
	SRR19660804.fastq.gz	Fastqsanger.gz

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DYRK1A regulates B cell class switch recombination through phosphorylation of MSH6

Project description:Effective protection from viral infections depends on the antibody-specific isotype. Here, we found that the protein kinase, DYRK1A, is essential for B cell-mediated protection from viral infection and vaccination through regulation of class switch recombination (CSR). Dyrk1a-deficient B cells were impaired in CSR activity in vivo and in vitro. Phospho-proteomic screens and kinase-activity assays identified MSH6, a DNA mismatch repair protein, as a direct substrate for DYRK1A, and deletion of a single phosphorylation site attenuated CSR. After CSR and germinal center seeding, DYRK1A was required for proper clonal expansion of antigen-specific B cells through attenuation of proliferation. These findings reveal DYRK1A-mediated biological mechanisms of antibody-mediated immune responses that may be used for manipulation in antibody-mediated autoimmunity

2022-11-27 | GSE206146 | GEO

DYRK1A regulates B cell class switch recombination through phosphorylation of MSH6

2023-03-16 | PXD034156 | Pride

DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination

Project description:The DNA-dependent protein kinase (DNA-PK), which is composed of the KU heterodimer and the large catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor. Naïve B cells undergo class switch recombination (CSR) to generate antibodies with different isotypes by joining two DNA double-strand breaks at different switching regions via the cNHEJ pathway. DNA-PK and the cNHEJ pathway play important roles in the DNA repair phase of CSR. To initiate cNHEJ, KU binds to DNA ends and recruits and activates DNA-PK. Activated DNA-PK phosphorylates DNA-PKcs at the S2056 and T2609 clusters. Loss of T2609 cluster phosphorylation increases radiation sensitivity but whether T2609 phosphorylation has a role in physiological DNA repair remains elusive. Using the DNA-PKcs5A mouse model carrying alanine substitutions at the T2609 cluster, here we show that loss of T2609 phosphorylation of DNA-PKcs does not affect the CSR efficiency. Yet, the CSR junctions recovered from DNA-PKcs5A/5A B cells reveal increased chromosomal translocations, extensive use of distal switch regions (consistent with end-resection), and preferential usage of micro-homology – all signs of the alternative end-joining pathway. Thus, these results uncover a role of DNA-PKcs T2609 phosphorylation in promoting cNHEJ repair pathway choice during CSR.

2020-07-18 | GSE154210 | GEO

B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation.

Project description:Protection from viral infections depends on immunoglobulin isotype switching, which endows antibodies with effector functions. Here, we find that the protein kinase DYRK1A is essential for B cell-mediated protection from viral infection and effective vaccination through regulation of class switch recombination (CSR). Dyrk1a-deficient B cells are impaired in CSR activity in vivo and in vitro. Phosphoproteomic screens and kinase-activity assays identify MSH6, a DNA mismatch repair protein, as a direct substrate for DYRK1A, and deletion of a single phosphorylation site impaired CSR. After CSR and germinal center (GC) seeding, DYRK1A is required for attenuation of B cell proliferation. These findings demonstrate DYRK1A-mediated biological mechanisms of B cell immune responses that may be used for therapeutic manipulation in antibody-mediated autoimmunity.

| S-EPMC10020581 | biostudies-literature

PTIP promotes chromatin changes critical for immunoglobulin class switch recombination

Project description:Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here we show that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3) /MLL4 complex display impaired histone methylation (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus leading to defective immunoglobulin class-switching. We also show that PTIP accumulation at DSBs contributes to class-switch recombination (CSR) and genome stability independently from Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR, and suggest a non-redundant role for the MLL3/MLL4 complex in altering antibody effector function. Genome-wide analysis of histone modifications, PTIP, and Pol II in PTIP-WT and PTIP-KO mouse activated B cells.

2010-08-25 | E-GEOD-20852 | biostudies-arrayexpress

Switch tandem repeats influence the choice of the alternative end-joining pathway in class switch recombination

Project description:Switch tandem repeats influence the choice of the alternative end-joining pathway in class switch recombination

2022-05-11 | GSE174296 | GEO

Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

Project description:We report here high-throughput sequencing analyses of class switch recombination junctions in Lsh deficient B cells with reduced capacity of class switch recombination compared to control B cells.

2020-07-30 | GSE150423 | GEO

PTIP promotes chromatin changes critical for immunoglobulin class switch recombination

2010-08-25 | GSE20852 | GEO

DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination

Project description:DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination

| PRJNA645427 | ENA

Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination

Project description:Class switch recombination generates antibody distinct isotypes critical to a robust adaptive immune system and defects are associated with auto-immune disorders and lymphomagenesis. Transcription is required during class switch to recruit the cytidine deaminase AID—an essential step for the formation of DNA doublestrand breaks—and strongly induces the formation of R loops within the immunoglobulin heavy chain locus. However, the impact of R loops on double-strand break formation and repair during class switch recombination remains unclear. Here we report that cells lacking two enzymes involved in R loop removal— Senataxin and RNase H2—exhibit increased R loop formation and genome instability at the immunoglobulin heavy chain locus without impacting class switch recombination efficiency, transcriptional activity, or AID recruitment. Senataxin and RNase H2-deficient cells also exhibit increased insertion mutations at switch junctions, a hallmark of alternative end joining. Importantly, these phenotypes were not observed in cells lacking Senataxin or RNase H2B alone. We propose that Senataxin acts redundantly with RNase H2 to mediate timely R loop removal, promoting efficient repair while suppressing AID-dependent genome instability and insertional mutagenesis.

2022-12-14 | GSE201210 | GEO

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