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RNA-binding proteins control the G2-M checkpoint of the germinal center B cell [TrAEL-seq]

ABSTRACT: The germinal center (GC) reaction drives the production of high-affinity antibodies by iterative cycles of B cell somatic hypermutation, selection, and proliferation. How GC B cells undergo rapid cell division while maintaining genome stability is poorly understood. Here, we show that the RNA binding proteins ZFP36L1 and ZFP36L2 act downstream of antigen sensing and protect GC B cells from replication stress by controlling a cell cycle-related posttranscriptional regulon. They safeguard the successful completion of mitosis by balancing CDK1 and p21-mediated regulation of cell-cycle progression. In their absence, GC B cells are prone to arrest in the G2-M phase and die by apoptosis, resulting in curtailed GC responses. DNA replication forks stalled at active replication initiation zones, causing replication stress and increased activity of the ATR-CHK1 DNA damage response. Thus, RNA binding proteins guide posttranscriptional gene regulation and maintain a functional G2-M checkpoint in GC B cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE279992 | GEO | 2024/10/24

REPOSITORIES: GEO

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RNA-binding proteins control the G2-M checkpoint of the germinal center B cell [RNAseq]

Project description:The germinal center (GC) reaction drives the production of high-affinity antibodies by iterative cycles of B cell somatic hypermutation, selection, and proliferation. How GC B cells undergo rapid cell division while maintaining genome stability is poorly understood. Here, we show that the RNA binding proteins ZFP36L1 and ZFP36L2 act downstream of antigen sensing and protect GC B cells from replication stress by controlling a cell cycle-related posttranscriptional regulon. They safeguard the successful completion of mitosis by balancing CDK1 and p21-mediated regulation of cell-cycle progression. In their absence, GC B cells are prone to arrest in the G2-M phase and die by apoptosis, resulting in curtailed GC responses. DNA replication forks stalled at active replication initiation zones, causing replication stress and increased activity of the ATR-CHK1 DNA damage response. Thus, RNA binding proteins guide posttranscriptional gene regulation and maintain a functional G2-M checkpoint in GC B cells.

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Project description:We report our study of the function of two members of the TTP (tristetraprolin) mRNA binding protein family, Zfp36l1 and Zfp36l2, in retinal development. We found that Zfp36l1 and Zfp36l2 were expressed in retinal progenitor cells during development and Müller glial cells and photoreceptors in the mature retina. Our analysis of the mutant retinas showed that, whereas the single knockout retinas appeared largely normal, the double knockout (DKO) retina manifested decreased RPC proliferation and increased differentiation of multiple retinal cell types. RNA-seq analysis not only confirmed the imbalance of proliferation and differentiation in the DKO retina but also revealed Zfp36l1 and Zfp36l2 interact with multiple signaling pathways including the sonic hedgehog pathway and the Notch pathway, to regulate this process.

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