The RNA-binding proteins Zfp36l1 and Zfp36l2 enforce the Thymic β-selection checkpoint by limiting DNA damage response signaling and cell cycle progression

Katharina U. Vogel, Lewis S. Bell, Alison Galloway, Helena Ahlfors, Martin Turner (Lead / Corresponding author)

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2673-2685
Number of pages13
JournalJournal of Immunology
Volume197
Issue number7
Early online date26 Aug 2016
DOIs
Publication statusPublished - 1 Oct 2016

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RNA-Binding Proteins
Thymocytes
DNA Damage
Interleukin-7
Cell Cycle
Chromosomal Instability
Cell Cycle Checkpoints
Transcriptome
Genome

Cite this

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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.",
author = "Vogel, {Katharina U.} and Bell, {Lewis S.} and Alison Galloway and Helena Ahlfors and Martin Turner",
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The RNA-binding proteins Zfp36l1 and Zfp36l2 enforce the Thymic β-selection checkpoint by limiting DNA damage response signaling and cell cycle progression. / Vogel, Katharina U.; Bell, Lewis S.; Galloway, Alison; Ahlfors, Helena; Turner, Martin (Lead / Corresponding author).

In: Journal of Immunology, Vol. 197, No. 7, 01.10.2016, p. 2673-2685.

Research output: Contribution to journalArticle

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AU - Galloway, Alison

AU - Ahlfors, Helena

AU - Turner, Martin

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