An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
07 07 2023
07 07 2023
Historique:
received:
22
11
2022
revised:
21
03
2023
accepted:
06
04
2023
medline:
10
7
2023
pubmed:
4
5
2023
entrez:
4
5
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37140445
pii: 726287
doi: 10.1158/2159-8290.CD-22-1315
pmc: PMC10326602
mid: NIHMS1893323
doi:
Substances chimiques
PADI4 protein, human
EC 3.5.3.15
Padi4 protein, mouse
EC 3.5.3.15
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1696-1719Subventions
Organisme : NCI NIH HHS
ID : R00 CA241367
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK050306
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006927
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009035
Pays : United States
Organisme : NIH HHS
ID : S10 OD030394
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA102184
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009171
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA238611
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA252025
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008216
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA252025
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
2023 The Authors; Published by the American Association for Cancer Research.
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