Distinct p53 isoforms code for opposing transcriptional outcomes

p53 genes are conserved transcriptional activators that respond to stress. These proteins can also downre-gulate 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 contin-uously through canonical DNA binding sites that confer p53-dependent transactivation at earlier develop-mental 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 tran-scriptional 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.

Automated summary

This study reveals opposing features of p53-mediated transcriptional control, with transcriptional repression being achieved through DNA binding sites and correlated with H3K9me3 chromatin marks, independent of stress or Chk2. Targeted knockout of different p53 isoforms dissociated their opposing transcriptional activities, highlighting their important roles in repression and proper germ cell formation.