The Naturally Occurring ∆40p53 Isoform Inhibits eRNA Transcription and Enables Context-Specific Regulation During p53 Activation
Social Science Research Network(2020)
摘要
The Δ40p53 isoform heterotetramerizes with WTp53 to regulate development, aging, and stress responses. How Δ40p53 alters WTp53 function remains enigmatic because their co-expression causes tetramer heterogeneity. We circumvented this issue with knock-in cell lines that generated homogeneous Δ40p53:WTp53 tetramers from the native TP53 locus, and examined with transcriptomics (PRO-seq, RNA-seq), metabolomics, and other methods. Although phenotypically similar to WTp53 under normal conditions, Δ40p53:WTp53 failed to induce growth arrest upon Nutlin-induced p53 activation. This occurred via Δ40p53:WTp53-dependent inhibition of eRNA transcription and subsequent failure to induce mRNA, despite similar genomic occupancy to WTp53. A different stimulus (5-fluorouracil) also showed Δ40p53:WTp53 defects in mRNA induction; however, other stimulus-specific TFs could then drive the response, yielding similar outcomes vs. WTp53. Our results define how Δ40p53 alters WTp53 function and identify an eRNA requirement for mRNA biogenesis. Moreover, Δ40p53:WTp53 functional distinctions uncovered herein suggest human p53 evolved as a tetramer to support eRNA transcription.
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