title: The RNA-Binding Proteins Zfp36l1 and Zfp36l2 Enforce the Thymic β-Selection Checkpoint by Limiting DNA Damage Response Signaling and Cell Cycle Progression.
abstract: 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.
authors: MedImmune, Granta Park Cambridge, CB21 6GH, UK.
authors: Katharina U
authors: KU
authors: Vogel
authors: Dept. of Medicine, University of Cambridge, MRC-Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
authors: Lewis S
authors: LS
authors: Bell
authors: Centre for Gene Regulation and Expression, School of Life Science, University of Dundee, Dundee DD1 5EH, UK.
authors: Alison
authors: A
authors: Galloway
authors: Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors: Helena
authors: H
authors: Ahlfors
authors: Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors: Martin
authors: M
authors: Turner
mesh_terms: D000818:Animals; D051817:Butyrate Response Factor 1; D002453:Cell Cycle / Q000276:immunology; D004249:DNA Damage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology* / Q000378:metabolism; D051816:Tristetraprolin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051817:Butyrate Response Factor 1; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; C488431:Zfp36l1 protein, mouse