PADI4 Regulates the p53 Pathway and Tumor Suppression Through Citrullination and Immune Activation / Alexandra Indeglia.

Format:

Book

Thesis/Dissertation

Author/Creator:

Indeglia, Alexandra, author.

Contributor:

University of Pennsylvania. Biochemistry and Molecular Biophysics, degree granting institution.

Language:

English

Subjects (All):

Biochemistry.

Molecular biology.

Cellular biology.

Biochemistry and Molecular Biophysics--Penn dissertations.

Penn dissertations--Biochemistry and Molecular Biophysics.

Local Subjects:

Biochemistry.

Molecular biology.

Cellular biology.

Biochemistry and Molecular Biophysics--Penn dissertations.

Penn dissertations--Biochemistry and Molecular Biophysics.

Physical Description:

1 online resource (189 pages)

Contained In:

Dissertations Abstracts International 85-12B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Ann Arbor : ProQuest Dissertations & Theses, 2024

Language Note:

English

Summary:

TP53 is the most frequently mutated gene in human cancer. While it is well understood that the ability of p53 to act as a transcription factor is required for tumor suppression, the key target genes downstream of p53 required for tumor suppression are still incompletely understood. We first set out to characterize a rare, African-specific, germline variant of TP53 in the DNA binding domain, Tyr107His (Y107H). Although we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes, Y107H mice develop spontaneous cancers and metastases. We identified the p53 target gene, PADI4, to be exquisitely sensitive to p53 mutation, and loss of PADI4 is seen in Y107H and other transcriptionally competent p53 hypomorphs. PADI4 is a regulator of histone modification and gene transcription via citrullination, which is the process of deiminating arginine to the non-natural amino acid citrulline. Our TCGA analysis reveals PADI4 is downregulated or mutated in multiple human cancers. Surprisingly, we show that PADI4 is sufficient to suppress tumor growth and sensitize wild-type p53 cells to chemotherapeutics. We further show that PADI4 is potently tumor suppressive in vivo, and complete tumor suppression by PADI4 requires an intact immune system. We find PADI4 enhances the transactivation of p53 targets and genes involved in immune activation. In addition, we identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors. We have further found that PADI4 interacts and modifies p53 via citrullination at key residues within the oligomerization and C-terminal domain of p53. PADI4 colocalizes with p53 on chromatin at non-canonical p53 target genes and genes devoid of a p53 response element. Citrullination of p53 may alter p53 function through enhanced oligomerization or binding of p53 to DNA. The findings from this study reveal PADI4 as not only a key target gene of p53, but a core regulator of p53 activity and target specificity through a novel protein modification. This work highlights the need to reassess the role of PADI4 in cancer, and provides insight into critical downstream target genes important for tumor suppression by p53.

Notes:

Source: Dissertations Abstracts International, Volume: 85-12, Section: B.

Advisors: Murphy, Maureen E.; Committee members: Wellen, Kathryn; Wan, Liling; Gardini, Alessandro; Keith, Brian.

Department: Biochemistry and Molecular Biophysics.

Ph.D. University of Pennsylvania 2024.

Local Notes:

School code: 0175

ISBN:

9798382836027

Access Restriction:

Restricted for use by site license.