ZNF509S1 downregulates PUMA by inhibiting p53K382 acetylation and p53-DNA binding

Biochim Biophys Acta Gene Regul Mech. 2017 Sep;1860(9):962-972. doi: 10.1016/j.bbagrm.2017.07.008. Epub 2017 Jul 27.


Expression of the POK family protein ZNF509L, and -its S1 isoform, is induced by p53 upon exposure to genotoxic stress. Due to alternative splicing of the ZNF509 primary transcript, ZNF509S1 lacks the 6 zinc-fingers and C-terminus of ZNF509L, resulting in only one zinc-finger. ZNF509L and -S1 inhibit cell proliferation by activating p21/CDKN1A and RB transcription, respectively. When cells are exposed to severe DNA damage, p53 activates PUMA (p53-upregulated modulator of apoptosis) transcription. Interestingly, apoptosis due to transcriptional activation of PUMA by p53 is attenuated by ZNF509S1. Thus we investigated the molecular mechanism(s) underlying the transcriptional attenuation and anti-apoptotic effects of ZNF509S1. We show that ZNF509S1 modulation of p53 activity is important in PUMA gene transcription by modulating post-translational modification of p53 by p300. ZNF509S1 directly interacts with p53 and inhibits p300-mediated acetylation of p53 lysine K382, with deacetylation of p53 K382 leading to decreased DNA binding at the p53 response element 1 of the PUMA promoter. ZNF509S1 may play a role not only in cell cycle arrest, by activating RB expression, but also in rescuing cells from apoptotic death by repressing PUMA expression in cells exposed to severe DNA damage.

Keywords: Apoptosis; PUMA; Post-translational modification; ZNF509S1 (ZBTB49); p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA / metabolism*
  • DNA Damage / physiology
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation / physiology*
  • E1A-Associated p300 Protein
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Promoter Regions, Genetic / physiology
  • Protein Binding / physiology
  • Protein Processing, Post-Translational / physiology
  • Puma / metabolism*
  • Transcriptional Activation / physiology
  • Tumor Suppressor Protein p53 / metabolism*
  • Zinc Fingers / physiology


  • Apoptosis Regulatory Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ZBTB49 protein, human
  • DNA
  • E1A-Associated p300 Protein
  • EP300 protein, human