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Targeted citrullination enables p53 binding to non-canonical sites
Alexandra Indeglia1, Andrea Valdespino2, Giulia Pantella3
1Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Molecular Cell
|October 3, 2025
Summary
The peptidyl-arginine deiminase 4 (PADI4) enzyme citrullinates the p53 protein, altering its DNA binding. This modification redirects p53 to new target genes, influencing cellular responses to stress.
Area of Science:
- Molecular Biology
- Gene Regulation
- Epigenetics
Background:
- The tumor suppressor protein p53 (TP53) regulates gene expression in response to cellular stress.
- The precise mechanisms governing p53's promoter selectivity remain unclear.
- Peptidyl-arginine deiminase 4 (PADI4) is involved in protein modification through citrullination.
Purpose of the Study:
- To investigate the role of PADI4 in regulating p53 sequence-specific DNA binding.
- To identify specific sites of p53 citrullination by PADI4.
- To determine how PADI4-mediated citrullination affects p53's transcriptional targets.
Main Methods:
- In vitro enzymatic assays to assess p53 citrullination by PADI4.
- Cellular and tissue analysis to confirm citrullination sites (R306, R363).
- Chromatin immunoprecipitation sequencing (ChIP-seq) to map p53 binding sites.
- Use of citrullination-specific p53 antibodies for chromatin profiling.
Main Results:
- PADI4 directly citrullinates p53 at the C terminus, specifically at R306 and R363.
- PADI4 expression redirects p53 binding from canonical sites.
- p53 is redirected to target genes associated with ETS transcription factors.
- Citrullination-specific antibodies confirm the altered p53 binding profile.
Conclusions:
- Citrullination by PADI4 is a novel regulatory mechanism for p53.
- PADI4 directs p53's promoter selectivity, influencing its transcriptional output.
- This study links protein citrullination to the regulation of the p53 tumor suppressor pathway.
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