Impact of proteasome inhibition on nascent transcription of APOBEC3 cytidine deaminases
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PROVIDER: PRJNA1041408 | ENA |
REPOSITORIES: ENA
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Project description:To assess the impact of the proteasome inhibitor MG132 on nascent transcription inMDA-MB-453 cells, csRNA-seq was conducted to compare transcript abundances between treated and DMSO control cells. Analysis of transcripts following MG132 treatment showed that APOBEC3A is one of the most differentially expressed genes. Comparison to other APOBEC family genes, revealed APOBEC3A is unique in its transcriptional upregulation by MG132. Analysis of transcription factor binding sites enriched in the promoter regions of genes changed greater than 2-fold in expression highlighted potential transcription factors driving increased APOBEC3A transcription.
2023-12-05 | GSE248016 | GEO
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.
2024-04-16 | PXD044275 | Pride
Project description:The human genome contains 11 APOBEC (Apolipoprotein B mRNA Editing Catalytic Polypeptide-like) cytidine deaminases classified into four families. These proteins function mainly in innate antiviral immunity and can also restrict endogenous retrotransposable element multiplication. The present study focuses on APOBEC3C (A3C), a member of the APOBEC3 sub-family. Some APOBEC3 proteins use their enzymatic activity on genomic DNA, inducing mutations and DNA damage, while other members facilitate DNA repair. Our results show that A3C is highly expressed in cells treated with DNA damaging agents. Its expression is regulated by p53. In addition, we provide the A3C interactome in both normal conditions and in cells exposed to the genotoxin etoposide. Most A3C interacting partners are proteins involved in RNA metabolism and some in DNA repair. Our data also indicate that A3C overexpression is detrimental to mammalian cells and we show that this protein is located around the nucleolus and at laser-damaged DNA sites.
2022-02-07 | PXD020105 | Pride
Project description:Nucleic acid editing enzymes are essential components of the human immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins. Among these enzymes are cytidine deaminases of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) super family, each with unique target sequence specificity and subcellular localization. We focus on the DNA-editing APOBEC3 enzymes that have recently attracted attention because of their involvement in cancer and potential in gene-editing applications. We review and compare the crystal structures of APOBEC3 (A3) domains, binding interactions with DNA, substrate specificity, and activity. Recent crystal structures of A3A and A3G bound to ssDNA have provided insights into substrate binding and specificity determinants of these enzymes. Still many unknowns remain regarding potential cooperativity, nucleic acid interactions, and systematic quantification of substrate preference of many APOBEC3s, which are needed to better characterize the biological functions and consequences of misregulation of these gene editors.
| S-EPMC6699113 | biostudies-literature
Project description:Foamy viruses (FVs) are nonpathogenic retroviruses infecting many species of mammals, notably primates, cattle, and cats. We have examined whether members of the apolipoprotein B-editing catalytic polypeptide-like subunit (APOBEC) family of antiviral cytidine deaminases restrict replication of simian FV. We show that human APOBEC3G is a potent inhibitor of FV infectivity in cell culture experiments. This antiviral activity is associated with cytidine editing of the viral genome. Both molecular FV clones and primary uncloned viruses were susceptible to APOBEC3G, and viral infectivity was also inhibited by murine and simian APOBEC3G homologues, as well as by human APOBEC3F. Wild-type and bet-deleted viruses were similarly sensitive to this antiviral activity, suggesting that Bet does not significantly counteract APOBEC proteins. Moreover, we did not detect FV sequences that may have been targeted by APOBEC in naturally infected macaques, but we observed a few G-to-A substitutions in humans that have been accidentally contaminated by simian FV. In infected hosts, the persistence strategy employed by FV might be based on low levels of replication, as well as avoidance of cells expressing large amounts of active cytidine deaminases.
| S-EPMC1346872 | biostudies-literature
Project description:BackgroundA mechanism of innate antiviral immunity operating against viruses infecting mammalian cells has been described during the last decade. Host cytidine deaminases ( e.g., APOBEC3 proteins) edit viral genomes, giving rise to hypermutated nonfunctional viruses; consequently, viral fitness is reduced through lethal mutagenesis. By contrast, sub-lethal hypermutagenesis may contribute to virus evolvability by increasing population diversity. To prevent genome editing, some viruses have evolved proteins that mediate APOBEC3 degradation. The model plant Arabidopsis thaliana genome encodes nine cytidine deaminases ( AtCDAs), raising the question of whether deamination is an antiviral mechanism in plants as well.MethodsHere we tested the effects of expression of AtCDAs on the pararetrovirus Cauliflower mosaic virus (CaMV). Two different experiments were carried out. First, we transiently overexpressed each one of the nine A. thalianaAtCDA genes in Nicotianabigelovii plants infected with CaMV, and characterized the resulting mutational spectra, comparing them with those generated under normal conditions. Secondly, we created A. thaliana transgenic plants expressing an artificial microRNA designed to knock-out the expression of up to six AtCDA genes. This and control plants were then infected with CaMV. Virus accumulation and mutational spectra where characterized in both types of plants.Results We have shown that the A. thalianaAtCDA1 gene product exerts a mutagenic activity, significantly increasing the number of G to A mutations in vivo, with a concomitant reduction in the amount of CaMV genomes accumulated. Furthermore, the magnitude of this mutagenic effect on CaMV accumulation is positively correlated with the level of AtCDA1 mRNA expression in the plant.ConclusionsOur results suggest that deamination of viral genomes may also work as an antiviral mechanism in plants.
| S-EPMC5461918 | biostudies-literature
Project description:<p><b>Reprinted from Roberts et al. "An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers", Nature Genetics, 45:970-976, 2013, with permission of Nature Publishing Group:</b></p> <p>Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas (TCGA), showed a significant presence of the APOBEC mutation pattern in bladder, cervical, breast, head and neck, and lung cancers, reaching 68% of all mutations in some samples. Within breast cancer, the HER2-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.</p>
| phs000677 | dbGaP
Project description:Nucleobase editors represent an emerging technology that enables precise single-base edits to the genomes of eukaryotic cells. Most nucleobase editors use deaminase domains that act upon single-stranded DNA and require RNA-guided proteins such as Cas9 to unwind the DNA prior to editing. However, the most recent class of base editors utilizes a deaminase domain, DddAtox, that can act upon double-stranded DNA. Here, we target DddAtox fragments and a FokI-based nickase to the human CIITA gene by fusing these domains to arrays of engineered zinc fingers (ZFs). We also identify a broad variety of Toxin-Derived Deaminases (TDDs) orthologous to DddAtox that allow us to fine-tune properties such as targeting density and specificity. TDD-derived ZF base editors enable up to 73% base editing in T cells with good cell viability and favorable specificity.
2024-01-12 | GSE253182 | GEO
Project description:Nucleobase editors represent an emerging technology that enables precise single-base edits to the genomes of eukaryotic cells. Most nucleobase editors use deaminase domains that act upon single-stranded DNA and require RNA-guided proteins such as Cas9 to unwind the DNA prior to editing. However, the most recent class of base editors utilizes a deaminase domain, DddAtox, that can act upon double-stranded DNA. Here, we target DddAtox fragments and a FokI-based nickase to the human CIITA gene by fusing these domains to arrays of engineered zinc fingers (ZFs). We also identify a broad variety of Toxin-Derived Deaminases (TDDs) orthologous to DddAtox that allow us to fine-tune properties such as targeting density and specificity. TDD-derived ZF base editors enable up to 73% base editing in T cells with good cell viability and favorable specificity.
2024-01-12 | GSE253184 | GEO