Distinct p53 isoforms code for opposing transcriptional outcomes

Annika Wylie, Amanda E Jones, Simanti Das, Wan Jin Lu, John M Abrams

Research output: Contribution to journalArticlepeer-review

Abstract

p53 genes are conserved transcriptional activators that respond to stress. These proteins can also downregulate genes, but the mechanisms are not understood and are generally assumed to be indirect. Here, we investigate synthetic and native cis-regulatory elements in Drosophila to examine opposing features of p53-mediated transcriptional control in vivo. We show that transcriptional repression by p53 operates continuously through canonical DNA binding sites that confer p53-dependent transactivation at earlier developmental stages. p53 transrepression is correlated with local H3K9me3 chromatin marks and occurs without the need for stress or Chk2. In sufficiency tests, two p53 isoforms qualify as transrepressors and a third qualifies as a transcriptional activator. Targeted isoform-specific knockouts dissociate these opposing transcriptional activities, highlighting features that are dispensable for transactivation but critical for repression and for proper germ cell formation. Together, these results demonstrate that certain p53 isoforms function as constitutive tissue-specific repressors, raising important implications for tumor suppression by the human counterpart.

Original languageEnglish (US)
Pages (from-to)1833-1846.e6
JournalDevelopmental cell
Volume57
Issue number15
DOIs
StatePublished - Aug 8 2022

Keywords

  • biosensor
  • Chk2
  • chromatin modifications
  • corolla
  • DNA binding motif
  • Drosophila
  • p53
  • p53 isoforms
  • transactivation
  • transrepression

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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