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.

p53 基因是对应激做出反应的保守转录激活因子。这些蛋白质也可以下调基因，但其机制尚不清楚，通常被认为是间接的。在这里，我们研究果蝇中的合成和天然顺式调节元件，以检查体内p53 介导的转录控制的相反特征。我们表明，p53 的转录抑制通过典型的 DNA 结合位点持续发挥作用，这些结合位点在早期发育阶段赋予 p53 依赖性反式激活。p53 反式抑制与局部 H3K9me3 染色质标记相关，并且无需应激或 Chk2 即可发生。在充分性测试中，两种 p53 亚型符合反式阻遏蛋白的资格，第三种符合转录激活剂的资格。靶向异构体特异性敲除分离了这些相反的转录活性，突出了反式激活可有可无但对于抑制和正确生殖细胞形成至关重要的特征。总之，这些结果表明某些 p53 同工型可作为组成型组织特异性阻遏物，这对人类对应物抑制肿瘤具有重要意义。