The RNA-Binding Proteins Zfp36l1 and Zfp36l2 Enforce the Thymic ?-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 ?-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 ?-selection. Double-negative 3 thymocytes lacking Zfp36l1/l2 share a gene expression profile with postselected double-negative 3b cells despite the absence of intracellular TCR? and reduced IL-7 signaling. Our findings show that in addition to controlling the timing of proliferation at ?-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.

SUBMITTER: Vogel KU 

PROVIDER: S-EPMC5027918 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature