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APOBEC3 promotes squamous differentiation and metastases via IL1A/AP-1 signaling

ABSTRACT: In urothelial carcinoma, up to 70% of mutations are caused by mutagenic activity of the APOBEC3 deaminases. To dissect the role of APOBEC3 in the progression of UC, we generated a mouse model UPPA with conditional knock out of Pten and Trp53 in addition to mouse Apobec3 (mA3) overexpression and scRNAseq was performed on the mouse bladder tumors.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE237016 | GEO | 2025/11/05

REPOSITORIES: GEO

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Protein interaction map of APOBEC3 enzyme family

Project description:Human APOBEC3 enzymes are a family of single-stranded (ss)DNA and RNA cytidine deaminases that act as part of the intrinsic immunity against viruses and retroelements. APOBEC3s deaminate cytosine to form uracil which can functionally inactivate or cause degradation of viral or retroelement genomes. In addition, APOBEC3 proteins have deamination independent anti-viral activity and aberrant regulation of APOBEC3 expression can result in the deamination and mutagenesis of the genome contributing to cancer initiation and evolution. To further understand their cellular roles, we used affinity purification mass spectrometry (AP-MS) to determine the protein-protein interaction (PPI) network for the human APOBEC3 enzymes and uncovered a diverse number of protein-protein and protein-RNA mediated interactions. PPIs with the Prefoldin family of protein folding chaperones were identified for APOBEC3B, APOBEC3D, and APOBEC3F. The APOBEC3B and prefoldin 5 (PFD5) interaction disrupted the ability of PFD5 to induce degradation of the oncogene cMyc, implicating a deamination independent contribution of APOBEC3B to cancer. Altogether, the results uncover novel functions and interactions of the APOBEC3 family and suggest that they may have fundamental roles in cellular RNA biology, their roles are not redundant, and there is a deamination independent influence on cancer.

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APOBEC3 promotes squamous differentiation and metastases via IL1A/AP-1 signaling

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Project description:Cell clones that lack P53 signaling occur frequently in ulcerative colitis (UC) and are considered drivers in UC-associated colorectal cancer. Trp53 mutant cells often display decreased P53 signaling and have previously been shown to outcompete wild type (WT) cells in a mouse model of colitis (DSS colitis), but not in healthy mice. However, the mechanism responsible for the observed context-dependent effects of P53 are not understood. Therefore, we aimed to explore this by studying the behavior of Trp53-deficient cells specifically in injured mucosa. We have developed murine and organoid-based models to study the context dependent role of Trp53 knock-out (KO). We use inducible KO systems in mouse models of DSS colitis to study the loss of Trp53 in the injury and regenerative state. Colon organoids are employed to recapitulate the in vivo findings in order to elucidate the pathways involved.

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Interaction with the CCT chaperonin complex limits cytotoxicity from the APOBEC3A cytosine deaminase.

Project description:The APOBEC3 cytosine deaminases are implicated as the cause of a prevalent somatic mutation pattern found in cancer genomes. The APOBEC3 enzymes act as viral restriction factors by mutating viral genomes. Mutation of the cellular genome is presumed to be an off-target activity of the enzymes, although the regulatory measures for APOBEC3 expression and activity remain undefined. It is therefore difficult to predict the circumstances that enable APOBEC3 interaction with cellular DNA that leads to mutagenesis. The APOBEC3A (A3A) enzyme is the most potent deaminase of the family. Using proteomics, we evaluated protein interactors of A3A to identify potential regulators. We found that A3A interacts with the Chaperonin Containing TCP-1 (CCT) complex, a cellular machine that assists in protein folding and function. Importantly, depletion of CCT resulted in increased A3A-induced cytotoxicity. Evaluation of cancer genomes demonstrated an enrichment of A3A mutational signatures in cancers with silencing mutations in CCT subunit genes. Together, these data suggest that the CCT complex interacts with A3A, and that disruption of CCT function results in increased A3A mutational activity.

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