An African-specific variant of TP53 reveals PADI4 as a regulator of p53-mediated tumor suppression

  • Cancer Discov. 2023 May 4;CD-22-1315. doi: 10.1158/2159-8290.CD-22-1315.
Alexandra Indeglia  1 ,  Jessica C Leung  1 ,  Sven A Miller  2 ,  Julia I-Ju Leu  3 ,  James F Dougherty  1 ,  Nicole L Clarke  1 ,  Nicole A Kirven  1 ,  Chunlei Shao  1 ,  Lei Ke  2 ,  Scott Lovell  4 ,  Thibaut Barnoud  1 ,  David Y Lu  1 ,  Cindy Lin  5 ,  Toshitha Kannan  1 ,  Kevin P Battaile  6 ,  Tyler Hong Loong Yang  5 ,  Isabela Batista Oliva  1 ,  Daniel T Claiborne  5 ,  Peter Vogel  7 ,  Lijun Liu  4 ,  Qin Liu  8 ,  Yulia Nefedova  5 ,  Joel Cassel  1 ,  Noam Auslander  1 ,  Andrew V Kossenkov  1 ,  John Karanicolas  2 ,  Maureen E Murphy  1
Affiliations
  • 1. The Wistar Institute, Philadelphia, PA, United States.
  • 2. Fox Chase Cancer Center, Philadelphia, PA, United States.
  • 3. Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
  • 4. University of Kansas, United States.
  • 5. The Wistar Institute, Philadelphia, Pennsylvania, United States.
  • 6. New York Structural Biology Center, United States.
  • 7. St. Jude Children's Research Hospital, Memphis, TN, United States.
  • 8. The Wistar Institute, Philadelphia, United States.
PMID: 37140445 DOI: 10.1158/2159-8290.CD-22-1315
Abstract

TP53 is the most frequently mutated gene in Cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific, germline variant of TP53 in the DNA binding domain, Tyr107His (Y107H). NMR and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the non-natural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases, and that Y107H shows impaired tumor suppression in two Other models. We show that PADI4 is itself tumor suppressive, and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune checkpoint inhibitors.

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