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The RNA-binding proteins Zfp36l1 and Zfp36l2 act redundantly to enforce the β-selection checkpoint during thymopoiesis, yet their molecular targets remain largely unknown. In this study, we identify these targets on a genome-wide scale in primary mouse thymocytes and show that Zfp36l1/l2 regulate DNA damage response and cell cycle transcripts to ensure proper β-selection. Double-negative 3 thymocytes lacking Zfp36l1/l2 share a gene expression profile with postselected double-negative 3b cells despite the absence of intracellular TCRβ and reduced IL-7 signaling. Our findings show that in addition to controlling the timing of proliferation at β-selection, posttranscriptional control by Zfp36l1/l2 limits DNA damage responses, which are known to promote thymocyte differentiation. Zfp36l1/l2 therefore act as posttranscriptional safeguards against chromosomal instability and replication stress by integrating pre-TCR and IL-7 signaling with DNA damage and cell cycle control.

Original publication

DOI

10.4049/jimmunol.1600854

Type

Journal article

Journal

J Immunol

Publication Date

01/10/2016

Volume

197

Pages

2673 - 2685

Keywords

Animals, Cell Cycle, DNA Damage, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nuclear Proteins, Phenotype, RNA-Binding Proteins, Signal Transduction, Thymocytes, Tristetraprolin