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A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies
bioRxiv - Developmental Biology Pub Date : 2020-10-12 , DOI: 10.1101/2020.06.24.167940
Gerald C. Tiu , Craig H. Kerr , Craig M. Forester , Pallavi S. Krishnarao , Hannah D. Rosenblatt , Nitin Raj , Olena Zhulyn , Margot E. Bowen , Leila Shokat , Laura D. Attardi , Davide Ruggero , Maria Barna

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

中文翻译:

p53依赖的翻译程序指导核糖体病模型中的组织选择性表型

在核糖体病中,核糖体成分的表达紊乱会导致组织特异性表型,例如肢体和颅面缺陷以及骨髓衰竭。核糖体(一种普遍存在的细胞机器)发生突变而导致这种组织选择性表现的原因仍然是个谜。结合全面的小鼠遗传学和体内核糖体分析,我们观察了核糖体蛋白(RP)单倍体不足胚胎中的肢体模式表型,并发现了控制肢体发育的转录本的相应选择性翻译变化。出人意料的是,由RP单倍体不足激活的p53的丢失和增加的蛋白质合成都挽救了这些表型。p53通过4E-BP1的转录激活充当蛋白质合成的主要调节剂,这一出乎意料的鉴定与这些发现相吻合。4E-BP1是翻译的关键调节因子,它又促进p53下游翻译组的选择性变化,从而至少部分解释RP单倍体不足如何引起基因表达的特异性。这些结果提供了一个综合模型来解释体内组织特异性表型如何从核糖体组分的突变中出现。
更新日期:2020-10-12
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