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The Naturally Occurring ∆40p53 Isoform Inhibits eRNA Transcription and Enables Context-Specific Regulation During p53 Activation
- Source :
- SSRN Electronic Journal.
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- 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.
Details
- ISSN :
- 15565068
- Database :
- OpenAIRE
- Journal :
- SSRN Electronic Journal
- Accession number :
- edsair.doi...........a44854c6c61d4af3eff60d9d832db512