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RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence

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Science  22 Apr 2016:
Vol. 352, Issue 6284, pp. 453-459
DOI: 10.1126/science.aad5978

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Reducing the risk of rearrangement

As lymphocytes develop, they rearrange their antigen receptor genes and proliferate extensively, potentially putting their genomes at risk. Galloway et al. found that two RNA-binding proteins, ZFP36L1 and ZFP36L2, ensure careful entry and exit into the cell cycle. This helps developing B lymphocytes maintain their genomic integrity. Mice deficient in ZFP36L1 and ZFP36L2 exhibited a profound block in B cell development. ZFP36L1 and ZFP36L2 suppress mRNAs that help B cells progress through the cell cycle, ensuring that cells can enter quiescence and keep their genomes safe when they undergo the risky process of rearranging their antigen receptors.

Science, this issue p. 453

Abstract

Progression through the stages of lymphocyte development requires coordination of the cell cycle. Such coordination ensures genomic integrity while cells somatically rearrange their antigen receptor genes [in a process called variable-diversity-joining (VDJ) recombination] and, upon successful rearrangement, expands the pools of progenitor lymphocytes. Here we show that in developing B lymphocytes, the RNA-binding proteins (RBPs) ZFP36L1 and ZFP36L2 are critical for maintaining quiescence before precursor B cell receptor (pre-BCR) expression and for reestablishing quiescence after pre-BCR–induced expansion. These RBPs suppress an evolutionarily conserved posttranscriptional regulon consisting of messenger RNAs whose protein products cooperatively promote transition into the S phase of the cell cycle. This mechanism promotes VDJ recombination and effective selection of cells expressing immunoglobulin-μ at the pre-BCR checkpoint.

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