A Genetic Screen Identifies TCF3/E2A and TRIAP1 as Pathway-Specific Regulators of the Cellular Response to p53 Activation

•A genomics approach for identification of gene-specific regulators•A shRNA screen identifies factors regulating the p21:PUMA ratio upon p53 activation•TCF3/E2A drives p21 expression while repressing PUMA•TRIAP1 is a gene-specific repressor of p21

SummaryThe p53 transcription factor participates in diverse cellular responses to stress, including cell-cycle arrest, apoptosis, senescence, and autophagy. The molecular mechanisms defining the ultimate outcome of p53 activation remain poorly characterized. We performed a genome-wide genetic screen in human cells to identify pathway-specific coregulators of the p53 target gene CDKN1A (p21), an inhibitor of cell-cycle progression, versus BBC3 (PUMA), a key mediator of apoptosis. Our screen identified numerous factors whose depletion creates an imbalance in the p21:PUMA ratio upon p53 activation. The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins. Accordingly, TCF3/E2A depletion impairs the cell-cycle-arrest response and promotes apoptosis upon p53 activation by chemotherapeutic agents. In contrast, TRIAP1 is a specific repressor of p21 whose depletion slows down cell-cycle progression. Our results reveal strategies for driving cells toward specific p53-dependent responses.

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