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Current Opinion in Structural Biology Apr 2021APOBEC3 enzymes are key enzymes in our innate immune system regulating antiviral response in HIV and unfortunately adding diversity in cancer as they deaminate cytosine.... (Review)
Review
APOBEC3 enzymes are key enzymes in our innate immune system regulating antiviral response in HIV and unfortunately adding diversity in cancer as they deaminate cytosine. Seven unique single and double domain APOBEC3s provide them with unique activity and specificity profiles for this deamination. Recent crystal and NMR structures of APOBEC3 complexes are unraveling the variety of epitopes involved in binding nucleic acids, including at the catalytic site, elsewhere on the catalytic domain and in the inactive N-terminal domain. The interplay between these diverse interactions is critical to uncovering the mechanisms by which APOBEC3s recognize and process their substrates.
Topics: APOBEC Deaminases; DNA; RNA
PubMed: 33486429
DOI: 10.1016/j.sbi.2020.12.004 -
Viruses Jun 2021The transmission of viruses from animal hosts into humans have led to the emergence of several diseases. Usually these cross-species transmissions are blocked by host... (Review)
Review
The transmission of viruses from animal hosts into humans have led to the emergence of several diseases. Usually these cross-species transmissions are blocked by host restriction factors, which are proteins that can block virus replication at a specific step. In the natural virus host, the restriction factor activity is usually suppressed by a viral antagonist protein, but this is not the case for restriction factors from an unnatural host. However, due to ongoing viral evolution, sometimes the viral antagonist can evolve to suppress restriction factors in a new host, enabling cross-species transmission. Here we examine the classical case of this paradigm by reviewing research on APOBEC3 restriction factors and how they can suppress human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). APOBEC3 enzymes are single-stranded DNA cytidine deaminases that can induce mutagenesis of proviral DNA by catalyzing the conversion of cytidine to promutagenic uridine on single-stranded viral (-)DNA if they escape the HIV/SIV antagonist protein, Vif. APOBEC3 degradation is induced by Vif through the proteasome pathway. SIV has been transmitted between Old World Monkeys and to hominids. Here we examine the adaptations that enabled such events and the ongoing impact of the APOBEC3-Vif interface on HIV in humans.
Topics: APOBEC Deaminases; Animals; Gene Products, vif; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Lentivirus Infections; Lentiviruses, Primate; Protein Binding; Protein Isoforms; Structure-Activity Relationship; Viral Zoonoses; vif Gene Products, Human Immunodeficiency Virus
PubMed: 34200141
DOI: 10.3390/v13061084 -
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 -
Chemical Reviews Oct 2016The AID/APOBEC family enzymes convert cytosines in single-stranded DNA to uracils, causing base substitutions and strand breaks. They are induced by cytokines produced... (Review)
Review
The AID/APOBEC family enzymes convert cytosines in single-stranded DNA to uracils, causing base substitutions and strand breaks. They are induced by cytokines produced during the body's inflammatory response to infections, and they help combat infections through diverse mechanisms. AID is essential for the maturation of antibodies and causes mutations and deletions in antibody genes through somatic hypermutation (SHM) and class-switch recombination (CSR) processes. One member of the APOBEC family, APOBEC1, edits mRNA for a protein involved in lipid transport. Members of the APOBEC3 subfamily in humans (APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H) inhibit infections of viruses such as HIV-1, HBV, and HCV, and retrotransposition of endogenous retroelements through mutagenic and nonmutagenic mechanisms. There is emerging consensus that these enzymes can cause mutations in the cellular genome at replication forks or within transcription bubbles depending on the physiological state of the cell and the phase of the cell cycle during which they are expressed. We describe here the state of knowledge about the structures of these enzymes, regulation of their expression, and both the advantageous and deleterious consequences of their expression, including carcinogenesis. We highlight similarities among them and present a holistic view of their regulation and function.
Topics: APOBEC Deaminases; Animals; Cytidine Deaminase; DNA; Mammals
PubMed: 27585283
DOI: 10.1021/acs.chemrev.6b00296 -
Mutation Research Jul 2018Cytosine and adenosine deamination events (DNA, RNA substrates) account for most codon-context Targeted Somatic Mutation (TSM) patterns observed in immunoglobulin (Ig)...
Cytosine and adenosine deamination events (DNA, RNA substrates) account for most codon-context Targeted Somatic Mutation (TSM) patterns observed in immunoglobulin (Ig) somatic hypermutation (SHM), and in cancer exomes following Ig-SHM-like responses. TSM refers to the process of somatic mutagenesis involving deamination events that results on a dominant type of mutation (e.g., C-to-T), and co-incident at a particular motif (e.g., WRC), and preferentially targeting the first, second or third nucleotide position within the mutated codon (e.g. MC1, MC2 or MC3, read 5-prime to 3-prime). It is now widely accepted that if left uncorrected, the accumulation of uncorrected TSMs involving the deaminases, may lead to a diagnosis of cancer or other degenerative disease. Our hypothesis is that many missense, nonsense and synonymous single nucleotide polymorphisms (SNPs) associated with clinically significant diseases may have arisen in the population by similar highly targeted deamination events. The OMIM database was searched for disease-associated SNPs on the X chromosome, and for all chromosomes. The nucleotide substitution patterns for disease-associated SNPs were analyzed by the TSM method to identify the likely deaminase source for C-to-U (C-to-T/G-to-A) and A-to-I (A-to-G/T-to-C) derived gene mutations preferentially targeting known sequence motifs associated with the deaminases: AID, APOBEC3G, APOBEC3B and ADAR 1/2. Of the 789 OMIM SNPs analysed. In both data sets, the mutation targeting preferences within the mutated codon reveal a statistically significant bias (p < 0.001). The results imply that a deamination of C-site and A-site targets are written into the human germline for the chromosome wide exomic SNPs analysed. This is consistent with previously observed mutation patterns arising in cancer genomes and hypermutated Ig genes during SHM. The results imply that similar types of deaminase-mediated molecular processes that occur in somatic hypermutation and cancer, may be contributing causative drivers of human exomic SNPs.
Topics: APOBEC Deaminases; APOBEC-3G Deaminase; Adenosine Deaminase; Complementarity Determining Regions; Cytidine Deaminase; Databases, Genetic; Humans; Minor Histocompatibility Antigens; Mutation; Polymorphism, Single Nucleotide; RNA-Binding Proteins; Somatic Hypermutation, Immunoglobulin
PubMed: 29957488
DOI: 10.1016/j.mrfmmm.2018.03.008 -
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 -
RNA Biology Sep 2017Apolipoprotein B mRNA Editing Catalytic Polypeptide-like 1 or APOBEC1 was discovered in 1993 as the zinc-dependent cytidine deaminase responsible for the production of... (Review)
Review
Apolipoprotein B mRNA Editing Catalytic Polypeptide-like 1 or APOBEC1 was discovered in 1993 as the zinc-dependent cytidine deaminase responsible for the production of an in frame stop codon in apoB mRNA through modification of cytidine at nucleotide position 6666 to uridine. At the time of this discovery there was much speculation concerning the mechanism of base modification RNA editing which has been rekindled by the discovery of multiple C to U RNA editing events in the 3' UTRs of mRNAs and the finding that other members of the APOBEC family while able to bind RNA, have the biological function of being DNA mutating enzymes. Current research is addressing the mechanism for these nucleotide modification events that appear not to adhere to the mooring sequence-dependent model for APOBEC1 involving the assembly of a multi protein containing editosome. This review will summarize our current understanding of the structure and function of APOBEC proteins and examine how RNA binding to them may be a regulatory mechanism.
Topics: APOBEC Deaminases; Animals; Catalytic Domain; Genetic Association Studies; Humans; Multigene Family; Protein Binding; Protein Interaction Domains and Motifs; Protein Multimerization; RNA; RNA Editing; Structure-Activity Relationship; Substrate Specificity
PubMed: 27869537
DOI: 10.1080/15476286.2016.1259783 -
Cancer Discovery Jul 2015Deep sequencing technologies are revealing the complexities of cancer evolution, casting light on mutational processes fueling tumor adaptation, immune escape, and... (Review)
Review
UNLABELLED
Deep sequencing technologies are revealing the complexities of cancer evolution, casting light on mutational processes fueling tumor adaptation, immune escape, and treatment resistance. Understanding mechanisms driving cancer diversity is a critical step toward developing strategies to attenuate tumor evolution and adaptation. One emerging mechanism fueling tumor diversity and subclonal evolution is genomic DNA cytosine deamination catalyzed by APOBEC3B and at least one other APOBEC family member. Deregulation of APOBEC3 enzymes causes a general mutator phenotype that manifests as diverse and heterogeneous tumor subclones. Here, we summarize knowledge of the APOBEC DNA deaminase family in cancer, and their role as driving forces for intratumor heterogeneity and a therapeutic target to limit tumor adaptation.
SIGNIFICANCE
APOBEC mutational signatures may be enriched in tumor subclones, suggesting APOBEC cytosine deaminases fuel subclonal expansions and intratumor heterogeneity. APOBEC family members might represent a new class of drug target aimed at limiting tumor evolution, adaptation, and drug resistance.
Topics: APOBEC Deaminases; Cytidine Deaminase; Cytosine; Cytosine Deaminase; Deamination; Evolution, Molecular; Genetic Heterogeneity; Humans; Mutation; Neoplasms
PubMed: 26091828
DOI: 10.1158/2159-8290.CD-15-0344 -
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 -
Journal of Hematology & Oncology Mar 2023Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs) are cytosine deaminases involved in innate and adaptive immunity. However, some APOBEC family... (Review)
Review
Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs) are cytosine deaminases involved in innate and adaptive immunity. However, some APOBEC family members can also deaminate host genomes to generate oncogenic mutations. The resulting mutations, primarily signatures 2 and 13, occur in many tumor types and are among the most common mutational signatures in cancer. This review summarizes the current evidence implicating APOBEC3s as major mutators and outlines the exogenous and endogenous triggers of APOBEC3 expression and mutational activity. The review also discusses how APOBEC3-mediated mutagenesis impacts tumor evolution through both mutagenic and non-mutagenic pathways, including by inducing driver mutations and modulating the tumor immune microenvironment. Moving from molecular biology to clinical outcomes, the review concludes by summarizing the divergent prognostic significance of APOBEC3s across cancer types and their therapeutic potential in the current and future clinical landscapes.
Topics: Humans; Clinical Relevance; Neoplasms; Mutagenesis; Mutation; Peptides; Cytidine Deaminase; Tumor Microenvironment; APOBEC Deaminases
PubMed: 36978147
DOI: 10.1186/s13045-023-01425-5