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

ABSTRACT: The germinal centre (GC) is the site where high-affinity antibody-producing B cells selectively expand. This process requires multiple rounds of antigen-based selection that are coupled to intense proliferation and cell death. We found that the RNA-binding proteins ZFP36L1 and ZFP36L2 act as antigen-sensing and are key to control cell cycle progression of GC B cells, in particular at the G2-M checkpoint. They regulate entry into mitosis by repressing the expression of CDK1 and cyclin B1, and keeping their activity in check through regulation of the CDK inhibitor p21. In the absence of ZFP36L1 and ZFP36L2, GC B cells are arrested in G2-M phase, where they express high levels of phosphorylated histone H2A.X. This is associated to an unresolved stalling of the DNA replication fork at active origins, which causes replication stress, activates the ATR/CHK1 DNA damage response, prevents mitosis and promotes apoptosis. As a result, the GC response is curtailed in mice lacking ZFP36L1 and ZFP36L2. Altogether, our study shows how post-transcriptional regulation protects GC B cells from replication stress by controlling their cell cycle progression through G2-M checkpoint activation.

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 [iCLIP]

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