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

TY - JOUR

T1 - The RNA-binding proteins Zfp36l1 and Zfp36l2 enforce the Thymic β-selection checkpoint by limiting DNA damage response signaling and cell cycle progression

AU - Vogel, Katharina U.

AU - Bell, Lewis S.

AU - Galloway, Alison

AU - Ahlfors, Helena

AU - Turner, Martin

N1 - This work was supported by the Biotechnology and Biological Sciences Research Council, a Medical Research Council centenary award and project grant from Bloodwise (A.G.), and the Federation of European Biochemical Societies (K.U.V.).

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

U2 - 10.4049/jimmunol.1600854

DO - 10.4049/jimmunol.1600854

M3 - Article

C2 - 27566829

SN - 0022-1767

VL - 197

SP - 2673

EP - 2685

JO - Journal of Immunology

JF - Journal of Immunology

IS - 7

ER -