A P53-dependent Translational Program Directs Tissue-selective Phenotypes in a Model of Ribosomopathies

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2021 Jul 9

PMID 34242585

Citations 24

Authors

Gerald C Tiu

Craig H Kerr

Craig M Forester

Pallavi S Krishnarao

Hannah D Rosenblatt

Nitin Raj

Travis C Lantz

Olena Zhulyn

Margot E Bowen

Leila Shokat

Laura D Attardi

Davide Ruggero

Maria Barna

Affiliations

Soon will be listed here.

Abstract

In ribosomopathies, perturbed expression of ribosome components leads to tissue-specific phenotypes. What accounts for such tissue-selective manifestations as a result of mutations in the ribosome, a ubiquitous cellular machine, has remained a mystery. Combining mouse genetics and in vivo ribosome profiling, we observe limb-patterning phenotypes in ribosomal protein (RP) haploinsufficient embryos, and we uncover selective translational changes of transcripts that controlling limb development. Surprisingly, both loss of p53, which is activated by RP haploinsufficiency, and augmented protein synthesis rescue these phenotypes. These findings are explained by the finding that p53 functions as a master regulator of protein synthesis, at least in part, through transcriptional activation of 4E-BP1. 4E-BP1, a key translational regulator, in turn, facilitates selective changes in the translatome downstream of p53, and this thereby explains how RP haploinsufficiency may elicit specificity to gene expression. These results provide an integrative model to help understand how in vivo tissue-specific phenotypes emerge in ribosomopathies.

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