Homo sapiens
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PROVIDER: PRJNA226257 | ENA |
REPOSITORIES: ENA
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Project description:APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers
| PRJNA226256 | ENA
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:APOBEC cytidine deaminase enzymes play a crucial role in antiviral innate immunity as they introduce mutations in viral genomes, restrict viral replication, and promote host defense against infections. Special three-stranded nucleic acid structures, called R-loops, have been considered as efficient targets for APOBEC-mediated mutagenesis because they present an ideal substrate, a persistent single-stranded DNA, for the enzyme. However, the relationship between R-loops and APOBEC enzyme activity has not been verified and remains to be elucidated. Here, we reveal a mechanistic link between R-loop formation, APOBEC enzyme binding, and APOBEC mutagenesis at viral R-loop targets during virus infection. In a cellular model involving human T lymphoblastoid leukemia cells infected with Herpes simplex virus 1 (HSV-1), we show that APOBEC3A and APOBEC3G binding sites and mutagenesis signatures occur mainly in viral R-loop structures. C-to-T mutagenesis primarily targets R-loops, which are specifically concentrated in HSV-1 genes that are essential for virus assembly and function. Among these genes, we identified mutation hotspots resulting in amino acid changes, likely leading to inactivation of HSV-1 protein functions. Collectively, our findings show that viral R-loops serve as potent targets for APOBEC-induced mutagenesis, representing an effective strategy to inactivate essential viral proteins and compromise viral activity.
2026-03-11 | GSE284474 | GEO
Project description:APOBEC cytidine deaminase enzymes play a crucial role in antiviral innate immunity as they introduce mutations in viral genomes, restrict viral replication, and promote host defense against infections. Special three-stranded nucleic acid structures, called R-loops, have been considered as efficient targets for APOBEC-mediated mutagenesis because they present an ideal substrate, a persistent single-stranded DNA, for the enzyme. However, the relationship between R-loops and APOBEC enzyme activity has not been verified and remains to be elucidated. Here, we reveal a mechanistic link between R-loop formation, APOBEC enzyme binding, and APOBEC mutagenesis at viral R-loop targets during virus infection. In a cellular model involving human T lymphoblastoid leukemia cells infected with Herpes simplex virus 1 (HSV-1), we show that APOBEC3A and APOBEC3G binding sites and mutagenesis signatures occur mainly in viral R-loop structures. C-to-T mutagenesis primarily targets R-loops, which are specifically concentrated in HSV-1 genes that are essential for virus assembly and function. Among these genes, we identified mutation hotspots resulting in amino acid changes, likely leading to inactivation of HSV-1 protein functions. Collectively, our findings show that viral R-loops serve as potent targets for APOBEC-induced mutagenesis, representing an effective strategy to inactivate essential viral proteins and compromise viral activity.
2026-03-11 | GSE277995 | GEO
Project description:APOBEC cytidine deaminase enzymes play a crucial role in antiviral innate immunity as they introduce mutations in viral genomes, restrict viral replication, and promote host defense against infections. Special three-stranded nucleic acid structures, called R-loops, have been considered as efficient targets for APOBEC-mediated mutagenesis because they present an ideal substrate, a persistent single-stranded DNA, for the enzyme. However, the relationship between R-loops and APOBEC enzyme activity has not been verified and remains to be elucidated. Here, we reveal a mechanistic link between R-loop formation, APOBEC enzyme binding, and APOBEC mutagenesis at viral R-loop targets during virus infection. In a cellular model involving human T lymphoblastoid leukemia cells infected with Herpes simplex virus 1 (HSV-1), we show that APOBEC3A and APOBEC3G binding sites and mutagenesis signatures occur mainly in viral R-loop structures. C-to-T mutagenesis primarily targets R-loops, which are specifically concentrated in HSV-1 genes that are essential for virus assembly and function. Among these genes, we identified mutation hotspots resulting in amino acid changes, likely leading to inactivation of HSV-1 protein functions. Collectively, our findings show that viral R-loops serve as potent targets for APOBEC-induced mutagenesis, representing an effective strategy to inactivate essential viral proteins and compromise viral activity.
2026-03-11 | GSE277996 | GEO
Project description:Intratumoral genetic heterogeneity and mutational burden have been suggested to be the fuel and the source of resistance for many molecularly targeted therapies throughout a multitude of cancers. Emerging evidence indicates that tumor cells could hijack the powerful mutagenesis machinery mediated by the DNA deaminase APOBEC family proteins to intensify mutagenesis, promote intratumoral heterogeneity, and foster therapy resistance through a cell-autonomous mechanism. However, this mechanism has yet to be characterized. Utilizing prostate cancer (PCa) as a relevant model, we have identified the Synaptotagmin Binding Cytoplasmic RNA Interacting Protein (SYNCRIP) as a molecular brake for APOBEC-driven mutagenesis, intratumoral heterogeneity, and resistance to Androgen Receptor (AR) targeted therapies. Through a multi-disciplinary approach integrating bulk and single cell RNA-Seq (scRNA-Seq), whole-genome exome-sequencing (WES), and CRISPR library screening, we identified eight mutated resistance driver genes and revealed unparalleled details of how these heterogeneously aberrant subclones fuel the evolution of AR therapy resistance. For the first time, these findings exposed a cell-autonomous mechanism activating APOBEC-driven mutagenesis, consequently fueling mutational burden, genetic heterogeneity, and therapy resistance, and suggested that APOBEC proteins could be the potential therapeutic targets for preventing or overcoming resistance in PCa.
2023-07-20 | GSE202321 | GEO
Project description:Retroviruses cause lifelong infections resulting from their ability to thwart innate immunity. The Apobec family of cytidine deaminases are part of the innate immune response that recognizes and mutates foreign nucleic acids, including those from multiple viruses. Multiple retroviral antagonists of Apobecs have been identified, including mouse mammary tumor virus (MMTV)-encoded Rem protein. Previous experiments have shown that Rem-null MMTV or closely related TBLV proviruses from BALB/c tumors accumulate G-to-A and C-to-T mutations typical of Apobecs compared to wild-type proviruses expressing Rem. The difference in mutations between Rem-expressing and non-expressing MMTV strains largely disappeared in mice lacking the Apobec family member, activation-induced cytidine deaminase (AID). These results suggested that Rem is an AID antagonist. In this study, we attempted to study AID-mediated mutations of TBLV proviruses lacking Rem expression obtained from tumors in C57BL/6 (B6) wild-type and AID-knockout backgrounds. Surprisingly, no differences in G-to-A mutations were observed in TBLV proviruses regardless of Rem expression, yet such mutations were significantly reduced in proviruses obtained from mA3/AID-double knockout mice relative to those from wild-type B6 or AID-knockout mice. Many cellular mRNAs involving the innate immune response, but not Apobecs, were elevated in the absence relative to the presence of Rem expression on the B6 AID-knockout background. These results revealed that Apobec-mediated mutagenesis is dependent on mouse strain and suggested a second means of Rem-dependent immune evasion.
2024-04-16 | GSE263741 | GEO
Project description:Retroviruses cause lifelong infections resulting from their ability to thwart innate immunity. The Apobec family of cytidine deaminases are part of the innate immune response that recognizes and mutates foreign nucleic acids, including those from multiple viruses. Multiple retroviral antagonists of Apobecs have been identified, including mouse mammary tumor virus (MMTV)-encoded Rem protein. Previous experiments have shown that Rem-null MMTV or closely related TBLV proviruses from BALB/c tumors accumulate G-to-A and C-to-T mutations typical of Apobecs compared to wild-type proviruses expressing Rem. The difference in mutations between Rem-expressing and non-expressing MMTV strains largely disappeared in mice lacking the Apobec family member, activation-induced cytidine deaminase (AID). These results suggested that Rem is an AID antagonist. In this study, we attempted to study AID-mediated mutations of TBLV proviruses lacking Rem expression obtained from tumors in C57BL/6 (B6) wild-type and AID-knockout backgrounds. Surprisingly, no differences in G-to-A mutations were observed in TBLV proviruses regardless of Rem expression, yet such mutations were significantly reduced in proviruses obtained from mA3/AID-double knockout mice relative to those from wild-type B6 or AID-knockout mice. Many cellular mRNAs involving the innate immune response, but not Apobecs, were elevated in the absence relative to the presence of Rem expression on the B6 AID-knockout background. These results revealed that Apobec-mediated mutagenesis is dependent on mouse strain and suggested a second means of Rem-dependent immune evasion.
2024-04-15 | GSE263655 | GEO
Project description:Interventions: Blood samples(10 points) are collected after the first administration of capecitabine for pharmacokinetic analysis and cytidine deaminase activity measurement.
Primary outcome(s): To evaluate the correlation AUC of 5-DFUR/AUC of 5-DFCR ratio and cytidine deaminase activity.
Study Design: Single arm Non-randomized
| 2634538 | ecrin-mdr-crc