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Nutlin-Induced Apoptosis Is Specified by a Translation Program Regulated by PCBP2 and DHX30.
Cell Reports ( IF 7.5 ) Pub Date : 2020-03-31 , DOI: 10.1016/j.celrep.2020.03.011
Dario Rizzotto 1 , Sara Zaccara 1 , Annalisa Rossi 1 , Matthew D Galbraith 2 , Zdenek Andrysik 2 , Ahwan Pandey 2 , Kelly D Sullivan 2 , Alessandro Quattrone 1 , Joaquín M Espinosa 2 , Erik Dassi 1 , Alberto Inga 1
Affiliation  

Activation of p53 by the small molecule Nutlin can result in a combination of cell cycle arrest and apoptosis. The relative strength of these events is difficult to predict by classical gene expression analysis, leaving uncertainty as to the therapeutic benefits. In this study, we report a translational control mechanism shaping p53-dependent apoptosis. Using polysome profiling, we establish Nutlin-induced apoptosis to associate with the enhanced translation of mRNAs carrying multiple copies of an identified 3' UTR CG-rich motif mediating p53-dependent death (CGPD-motif). We identify PCBP2 and DHX30 as CGPD-motif interactors. We find that in cells undergoing persistent cell cycle arrest in response to Nutlin, CGPD-motif mRNAs are repressed by the PCBP2-dependent binding of DHX30 to the motif. Upon DHX30 depletion in these cells, the translation of CGPD-motif mRNAs increases, and the response to Nutlin shifts toward apoptosis. Instead, DHX30 inducible overexpression in SJSA1 cells leads to decreased translation of CGPD-motif mRNAs.

中文翻译:

Nutlin诱导的细胞凋亡由PCBP2和DHX30调控的翻译程序指定。

小分子Nutlin激活p53可导致细胞周期停滞和凋亡。这些事件的相对强度很难通过经典的基因表达分析来预测,因此在治疗效果方面还不确定。在这项研究中,我们报告了一个翻译控制机制,塑造了依赖p53的细胞凋亡。使用多核糖体分析,我们建立Nutlin诱导的细胞凋亡,以与携带多份已确定的3'UTR CG丰富基序介导p53依赖性死亡(CGPD-基序)的mRNA的增强翻译相关。我们将PCBP2和DHX30确定为CGPD-基序相互作用体。我们发现在细胞响应Nutlin经历持续的细胞周期停滞时,CGPD-基元mRNA被DHX30与基序的PCBP2依赖性结合所抑制。在这些细胞中DHX30耗尽后,CGPD基序mRNA的翻译增加,并且对Nutlin的应答向细胞凋亡转移。相反,在SJSA1细胞中DHX30诱导的过表达导致CGPD-motif mRNA的翻译减少。
更新日期:2020-03-31
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