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TRANSLATIONAL CONTROL OF PRO-APOPTOTIC PUMA VIA MRNA 5′ END REGULATORY ELEMENTS

Abstract

PUMA (p53 upregulated modulator of apoptosis) is a pro-apoptotic gene. PUMA interacts with Bcl-2 proteins causing apoptosis. Expression of PUMA is essential in both normal cell biology and cancer progression. While the transcriptional regulation of PUMA by the tumor suppressor p53 (in response to stress like DNA damage, hypoxia, and ER stress) is well-studied, the translational control mediated by its 5′ untranslated region (UTR) is poorly characterized. The 5′ UTR secondary structure is a likely regulatory hub for controlling initiation of protein synthesis. We applied the SHAPE-MaP chemical probing strategy to build a robust model of the PUMA mRNA 5′ UTR structure using RNA extracted from A549 human lung carcinoma cells. More significantly, we then reported distinct structural changes observed under in-cell conditions. These differences represent specific regions of RNA-protein interaction occurring on the critical 5′ regulatory element. We further employed RNP-MaP, which precisely maps RNA-protein complexes in live A549 cells. Future directions include conducting comparative structural and RNP interaction analyses of the PUMA 5′ UTR under specific chemically-induced stress conditions.

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