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Table S2 from An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression

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posted on 2023-07-07, 08:21 authored by Alexandra Indeglia, Jessica C. Leung, Sven A. Miller, Julia I-Ju Leu, James F. Dougherty, Nicole L. Clarke, Nicole A. Kirven, Chunlei Shao, Lei Ke, Scott Lovell, Thibaut Barnoud, David Y. Lu, Cindy Lin, Toshitha Kannan, Kevin P. Battaile, Tyler Hong Loong Yang, Isabela Batista Oliva, Daniel T. Claiborne, Peter Vogel, Lijun Liu, Qin Liu, Yulia Nefedova, Joel Cassel, Noam Auslander, Andrew V. Kossenkov, John Karanicolas, Maureen E. Murphy

Evaluating the association between AA, Y107H variant, and cancer risk.

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Institute of General Medical Sciences (NIGMS)

United States Department of Health and Human Services

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ARTICLE 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). Nuclear magnetic resonance 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 nonnatural 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. We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy.See related commentary by Bhatta and Cooks, p. 1518.This article is highlighted in the In This Issue feature, p. 1501

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    Cancer Discovery

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    cancer

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