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Cancers Jan 2024APOBEC cytosine deaminases are prominent mutators in cancer, mediating mutations in over 50% of cancers. APOBEC mutagenesis has been linked to tumor heterogeneity,...
APOBEC cytosine deaminases are prominent mutators in cancer, mediating mutations in over 50% of cancers. APOBEC mutagenesis has been linked to tumor heterogeneity, persistent cell evolution, and therapy responses. While emerging evidence supports the impact of APOBEC mutagenesis on cancer progression, the understanding of its contribution to cancer susceptibility and malignant transformation is limited. We examine the existing evidence for the role of APOBEC mutagenesis in carcinogenesis on the basis of the reported associations between germline polymorphisms in genes encoding APOBEC enzymes and cancer risk, insights into APOBEC activities from sequencing efforts of both malignant and non-malignant human tissues, and in vivo studies. We discuss key knowledge gaps and highlight possible ways to gain a deeper understanding of the contribution of APOBEC mutagenesis to cancer development.
PubMed: 38254863
DOI: 10.3390/cancers16020374 -
Clinical Cancer Research : An Official... May 2023Over recent years, members of the APOBEC3 family of cytosine deaminases have been implicated in increased cancer genome mutagenesis, thereby contributing to intratumor... (Review)
Review
Over recent years, members of the APOBEC3 family of cytosine deaminases have been implicated in increased cancer genome mutagenesis, thereby contributing to intratumor and intertumor genomic heterogeneity and therapy resistance in, among others, breast cancer. Understanding the available methods for clinical detection of these enzymes, the conditions required for their (dysregulated) expression, the clinical impact they have, and the clinical implications they may offer is crucial in understanding the current impact of APOBEC3-mediated mutagenesis in breast cancer. Here, we provide a comprehensive review of recent developments in the detection of APOBEC3-mediated mutagenesis and responsible APOBEC3 enzymes, summarize the pathways that control their expression, and explore the clinical ramifications and opportunities they pose. We propose that APOBEC3-mediated mutagenesis can function as a helpful predictive biomarker in several standard-of-care breast cancer treatment plans and may be a novel target for treatment.
Topics: Humans; Female; Breast Neoplasms; Mutagenesis; Cytosine Deaminase; Genome; Cytidine Deaminase; APOBEC Deaminases
PubMed: 36478188
DOI: 10.1158/1078-0432.CCR-22-2861 -
Trends in Genetics : TIG Nov 2021APOBEC proteins can deaminate cytosine residues in DNA and RNA. This can lead to somatic mutations, DNA breaks, RNA modifications, or DNA demethylation in a selective... (Review)
Review
APOBEC proteins can deaminate cytosine residues in DNA and RNA. This can lead to somatic mutations, DNA breaks, RNA modifications, or DNA demethylation in a selective manner. APOBECs function in various cellular compartments and recognize different nucleic acid motifs and structures. They orchestrate a wide array of genomic and epigenomic modifications, thereby affecting various cellular functions positively or negatively, including immune editing, viral and retroelement restriction, DNA damage responses, DNA demethylation, gene expression, and tissue homeostasis. Furthermore, the cumulative increase in genomic and epigenomic editing with aging could also, at least in part, be attributed to APOBEC function. We synthesize our cumulative understanding of APOBEC activity in a unifying overview and discuss their genomic and epigenomic impact in physiological, pathological, and technological contexts.
Topics: APOBEC Deaminases; Cytidine Deaminase; Epigenomics; Genome; Genomics; Retroelements
PubMed: 34353635
DOI: 10.1016/j.tig.2021.07.003 -
Cancer Research Feb 2023The APOBEC cytidine deaminase enzyme family is linked to mutational signatures identified in cancer. While previous work has provided insights into the role of APOBEC3A...
The APOBEC cytidine deaminase enzyme family is linked to mutational signatures identified in cancer. While previous work has provided insights into the role of APOBEC3A and APOBEC3B in mutational processes in cancer, understanding of the mutational signatures induced by other APOBEC family members is limited. In this issue of Cancer Research, Liu and colleagues investigated the role of APOBEC3G (A3G) in bladder cancer. The authors revealed that transgenic expression of A3G in a murine bladder cancer model promotes tumorigenesis and induces a unique mutational signature distinct from previously identified APOBEC signatures. Expression of this A3G-related mutational signature correlated with significantly worse survival in patients with urothelial bladder carcinoma, and A3G expression was identified in 21 different cancer types. These findings suggest that different APOBEC3 enzymes induce unique mutation signatures and play distinct roles in cancer evolution. More complete understanding of the function of each APOBEC3 enzyme will improve anticancer therapy. See related article by Liu et al., p. 506.
Topics: Humans; Animals; Mice; Mutagens; Mutagenesis; Cytidine Deaminase; Urinary Bladder Neoplasms; APOBEC-3G Deaminase; Clonal Evolution; Minor Histocompatibility Antigens
PubMed: 36789568
DOI: 10.1158/0008-5472.CAN-22-3598 -
BioRxiv : the Preprint Server For... Dec 2023Evolvability is an emergent hallmark of cancer that depends on intra-tumor heterogeneity and, ultimately, genetic variation. Mutations generated by APOBEC3 cytidine...
Evolvability is an emergent hallmark of cancer that depends on intra-tumor heterogeneity and, ultimately, genetic variation. Mutations generated by APOBEC3 cytidine deaminases can contribute to genetic variation and the consequences of APOBEC activation differ depending on the stage of cancer, with the most significant impact observed during the early stages. However, how APOBEC activity shapes evolutionary patterns of genes in the host genome and differential impacts on cancer-associated and non-cancer genes remain unclear. Analyzing over 40,000 human protein-coding transcripts, we identified distinct distribution patterns of APOBEC3A/B TC motifs between cancer-related genes and controls, suggesting unique associations with cancer. Studying a bat species with many more APOBEC3 genes, we found diverse motif patterns in orthologs of cancer genes compared to controls, similar to humans and suggesting APOBEC evolution to reduce impacts on the genome rather than the converse. Simulations confirmed that APOBEC-induced heterogeneity enhances cancer evolution, shaping clonal dynamics through bimodal introduction of mutations in certain classes of genes. Our results suggest that a major consequence of the bimodal distribution of APOBEC affects greater cancer heterogeneity.
PubMed: 38106028
DOI: 10.1101/2023.08.27.554991 -
Viruses Jan 2021The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses, including lentiviruses.... (Review)
Review
The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses, including lentiviruses. genes are highly amplified and diversified in mammals, suggesting that their evolution and diversification have been driven by conflicts with ancient viruses. At present, lentiviruses, including HIV, the causative agent of AIDS, are known to encode a viral protein called Vif to overcome the antiviral effects of the APOBEC3 proteins of their hosts. Recent studies have revealed that the acquisition of an anti-APOBEC3 ability by lentiviruses is a key step in achieving successful cross-species transmission. Here, we summarize the current knowledge of the interplay between mammalian APOBEC3 proteins and viral infections and introduce a scenario of the coevolution of mammalian genes and viruses.
Topics: APOBEC Deaminases; Animals; Disease Resistance; Evolution, Molecular; Genetic Variation; Genome, Viral; Host-Pathogen Interactions; Humans; Lentivirus; Phylogeny; Retroviridae; Retroviridae Infections; Species Specificity; vif Gene Products, Human Immunodeficiency Virus
PubMed: 33477360
DOI: 10.3390/v13010124 -
Circulation Nov 2021Loss of dystrophin protein causes Duchenne muscular dystrophy (DMD), characterized by progressive degeneration of cardiac and skeletal muscles, and mortality in...
BACKGROUND
Loss of dystrophin protein causes Duchenne muscular dystrophy (DMD), characterized by progressive degeneration of cardiac and skeletal muscles, and mortality in adolescence or young adulthood. Although cardiac failure has risen as the leading cause of mortality in patients with DMD, effective therapeutic interventions remain underdeveloped, in part, because of the lack of a suitable preclinical model.
METHODS
We analyzed a novel murine model of DMD created by introducing a 4-bp deletion into exon 4, one of the exons encoding the actin-binding domain 1 of dystrophin (referred to as mice). Echocardiography, microcomputed tomography, muscle force measurement, and histological analysis were performed to determine cardiac and skeletal muscle defects in these mice. Using this model, we examined the feasibility of using a cytidine base editor to install exon skipping and rescue dystrophic cardiomyopathy in vivo. AAV9-based CRISPR/Cas9-AID (eTAM) together with AAV9-sgRNA was injected into neonatal mice, which were analyzed 2 or 12 months after treatment to evaluate the extent of exon skipping, dystrophin restoration, and phenotypic improvements of cardiac and skeletal muscles.
RESULTS
mice recapitulated many aspects of human DMD, including shortened life span (by ≈50%), progressive cardiomyopathy, kyphosis, profound loss of muscle strength, and myocyte degeneration. A single-dose administration of AAV9-eTAM instituted >50% targeted exon skipping in the transcripts and restored up to 90% dystrophin in the heart. As a result, early ventricular remodeling was prevented and cardiac and skeletal muscle functions were improved, leading to an increased life span of the mice. Despite gradual decline of AAV vector and base editor expression, dystrophin restoration and pathophysiological rescue of muscular dystrophy were long lasted for at least 1 year.
CONCLUSIONS
Our study demonstrates the feasibility and efficacy to institute exon skipping through an enhanced TAM (eTAM) for therapeutic application(s).
Topics: APOBEC Deaminases; Animals; CRISPR-Cas Systems; Cardiomyopathies; Dependovirus; Dystrophin; Exons; Genetic Vectors; Humans; Mice; Mice, Inbred mdx; Muscular Dystrophy, Duchenne
PubMed: 34698513
DOI: 10.1161/CIRCULATIONAHA.121.054628 -
Journal of Pharmaceutical Analysis Aug 2021Coronaviruses are dangerous human and animal pathogens. The newly identified coronavirus SARS-CoV-2 is the causative agent of COVID-19 outbreak, which is a real threat... (Review)
Review
Coronaviruses are dangerous human and animal pathogens. The newly identified coronavirus SARS-CoV-2 is the causative agent of COVID-19 outbreak, which is a real threat to human health and life. The world has been struggling with this epidemic for about a year, yet there are still no targeted drugs and effective treatments are very limited. Due to the long process of developing new drugs, reposition of existing ones is one of the best ways to deal with an epidemic of emergency infectious diseases. Among the existing drugs, there are candidates potentially able to inhibit the SARS-CoV-2 replication, and thus inhibit the infection of the virus. Some therapeutics target several proteins, and many diseases share molecular paths. In such cases, the use of existing pharmaceuticals for more than one purpose can reduce the time needed to design new drugs. The aim of this review was to analyze the key targets of viral infection and potential drugs acting on them, as well as to discuss various strategies and therapeutic approaches, including the possible use of natural products. We highlighted the approach based on increasing the involvement of human deaminases, particularly APOBEC deaminases in editing of SARS-CoV-2 RNA. This can reduce the cytosine content in the viral genome, leading to the loss of its integrity. We also indicated the nucleic acid technologies as potential approaches for COVID-19 treatment. Among numerous promising natural products, we pointed out curcumin and cannabidiol as good candidates for being anti-SARS-CoV-2 agents.
PubMed: 33842018
DOI: 10.1016/j.jpha.2021.03.012 -
Molecular Metabolism Mar 2022In mammals, modifications to cytosine bases, particularly in cytosine-guanine (CpG) dinucleotide contexts, play a major role in shaping the epigenome. The canonical... (Review)
Review
BACKGROUND
In mammals, modifications to cytosine bases, particularly in cytosine-guanine (CpG) dinucleotide contexts, play a major role in shaping the epigenome. The canonical epigenetic mark is 5-methylcytosine (5mC), but oxidized versions of 5mC, including 5-hydroxymethylcytosine (5hmC), are now known to be important players in epigenomic dynamics. Understanding the functional role of these modifications in gene regulation, normal development, and pathological conditions requires the ability to localize these modifications in genomic DNA. The classical approach for sequencing cytosine modifications has involved differential deamination via the chemical sodium bisulfite; however, bisulfite is destructive, limiting its utility in important biological or clinical settings where detection of low frequency populations is critical. Additionally, bisulfite fails to resolve 5mC from 5hmC.
SCOPE OF REVIEW
To summarize how enzymatic rather than chemical approaches can be leveraged to localize and resolve different cytosine modifications in a non-destructive manner.
MAJOR CONCLUSIONS
Nature offers a suite of enzymes with biological roles in cytosine modification in organisms spanning from bacteriophages to mammals. These enzymatic activities include methylation by DNA methyltransferases, oxidation of 5mC by TET family enzymes, hypermodification of 5hmC by glucosyltransferases, and the generation of transition mutations from cytosine to uracil by DNA deaminases. Here, we describe how insights into the natural reactivities of these DNA-modifying enzymes can be leveraged to convert them into powerful biotechnological tools. Application of these enzymes in sequencing can be accomplished by relying on their natural activity, exploiting their ability to discriminate between cytosine modification states, reacting them with functionalized substrate analogs to introduce chemical handles, or engineering the DNA-modifying enzymes to take on new reactivities. We describe how these enzymatic reactions have been combined and permuted to localize DNA modifications with high specificity and without the destructive limitations posed by chemical methods for epigenetic sequencing.
Topics: Animals; Cytosine; DNA; DNA Methylation; Epigenomics; Gene Expression Regulation; Mammals
PubMed: 34375743
DOI: 10.1016/j.molmet.2021.101314 -
Journal of Translational Medicine Sep 2019Post-transcriptional modifications have been recently expanded with the addition of RNA editing, which is predominantly mediated by adenosine and cytidine deaminases... (Review)
Review
Post-transcriptional modifications have been recently expanded with the addition of RNA editing, which is predominantly mediated by adenosine and cytidine deaminases acting on DNA and RNA. Here, we review the full spectrum of physiological processes in which these modifiers are implicated, among different organisms. Adenosine to inosine (A-to-I) editors, members of the ADAR and ADAT protein families are important regulators of alternative splicing and transcriptional control. On the other hand, cytidine to uridine (C-to-U) editors, members of the AID/APOBEC family, are heavily implicated in innate and adaptive immunity with important roles in antibody diversification and antiviral response. Physiologically, these enzymes are present in the nucleus and/or the cytoplasm, where they modify various RNA molecules, including miRNAs, tRNAs apart from mRNAs, whereas DNA editing is also possible by some of them. The expansion of next generation sequencing technologies provided a wealth of data regarding such modifications. RNA editing has been implicated in various disorders including cancer, and neurological diseases of the brain or the central nervous system. It is also related to cancer heterogeneity and the onset of carcinogenesis. Response to treatment can also be affected by the RNA editing status where drug efficacy is significantly compromised. Studying RNA editing events can pave the way to the identification of new disease biomarkers, and provide a more personalised therapy to various diseases.
Topics: Animals; Cytidine Deaminase; Disease; Health; High-Throughput Nucleotide Sequencing; Humans; RNA Editing; Transcriptome
PubMed: 31547885
DOI: 10.1186/s12967-019-2071-4