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Cancer Discovery Oct 2021APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when expression is induced during cancer development remains to be defined. Here we show that...
APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when expression is induced during cancer development remains to be defined. Here we show that specific genes are upregulated in breast ductal carcinoma , and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non-small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. SIGNIFICANCE: This study reveals the dynamics and drivers of gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution..
Topics: APOBEC Deaminases; Animals; Breast Neoplasms; Carcinoma, Ductal; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chromosomal Instability; DNA Replication; Female; Humans; Lung Neoplasms; Mice
PubMed: 33947663
DOI: 10.1158/2159-8290.CD-20-0725 -
Nature Mar 2023The APOBEC3 (A3) proteins are host antiviral cellular proteins that hypermutate the viral genome of diverse viral families. In retroviruses, this process requires A3...
The APOBEC3 (A3) proteins are host antiviral cellular proteins that hypermutate the viral genome of diverse viral families. In retroviruses, this process requires A3 packaging into viral particles. The lentiviruses encode a protein, Vif, that antagonizes A3 family members by targeting them for degradation. Diversification of A3 allows host escape from Vif whereas adaptations in Vif enable cross-species transmission of primate lentiviruses. How this 'molecular arms race' plays out at the structural level is unknown. Here, we report the cryogenic electron microscopy structure of human APOBEC3G (A3G) bound to HIV-1 Vif, and the hijacked cellular proteins that promote ubiquitin-mediated proteolysis. A small surface explains the molecular arms race, including a cross-species transmission event that led to the birth of HIV-1. Unexpectedly, we find that RNA is a molecular glue for the Vif-A3G interaction, enabling Vif to repress A3G by ubiquitin-dependent and -independent mechanisms. Our results suggest a model in which Vif antagonizes A3G by intercepting it in its most dangerous form for the virus-when bound to RNA and on the pathway to packaging-to prevent viral restriction. By engaging essential surfaces required for restriction, Vif exploits a vulnerability in A3G, suggesting a general mechanism by which RNA binding helps to position key residues necessary for viral antagonism of a host antiviral gene.
Topics: Animals; Humans; APOBEC-3G Deaminase; HIV-1; RNA; Ubiquitin; vif Gene Products, Human Immunodeficiency Virus; Cryoelectron Microscopy; Proteolysis; Viral Genome Packaging; Primates
PubMed: 36754086
DOI: 10.1038/s41586-023-05779-1 -
Protein Science : a Publication of the... Sep 2019Nucleic acid editing enzymes are essential components of the human immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins. Among these... (Comparative Study)
Comparative Study Review
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.
Topics: APOBEC Deaminases; Binding Sites; DNA; Gene Editing; Humans; Protein Binding; Protein Conformation; Substrate Specificity
PubMed: 31241202
DOI: 10.1002/pro.3670 -
DNA Repair Oct 2020The APOBEC family of cytidine deaminases has been proposed to represent a major enzymatic source of mutations in cancer. Here, we summarize available evidence that links... (Review)
Review
The APOBEC family of cytidine deaminases has been proposed to represent a major enzymatic source of mutations in cancer. Here, we summarize available evidence that links APOBEC deaminases to cancer mutagenesis. We also highlight newly identified human cell models of APOBEC mutagenesis, including cancer cell lines with suspected endogenous APOBEC activity and a cell system of telomere crisis-associated mutations. Finally, we draw on recent data to propose potential causes of APOBEC misregulation in cancer, including the instigating factors, the relevant mutator(s), and the mechanisms underlying generation of the genome-dispersed and clustered APOBEC-induced mutations.
Topics: APOBEC Deaminases; Animals; Humans; Mutagenesis; Mutation; Neoplasms
PubMed: 32818816
DOI: 10.1016/j.dnarep.2020.102905 -
Viruses Jul 2021Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using... (Review)
Review
Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using deaminase and deaminase-independent mechanisms. These enzymes are essential components of our innate immune system, as evidenced by (a) their strong positive selection and expansion in primates, (b) the evolution of viral counter-defense mechanisms, such as proteasomal degradation mediated by HIV Vif, and (c) hypermutation and inactivation of a large number of integrated HIV-1 proviruses. Numerous APOBEC3 single nucleotide polymorphisms, haplotypes, and splice variants have been identified in humans. Several of these variants have been reported to be associated with differential antiviral immunity. This review focuses on the current knowledge in the field about these natural variations and their roles in infectious diseases.
Topics: APOBEC Deaminases; Cytidine Deaminase; Cytosine Deaminase; HIV-1; Hepatitis B virus; Host-Pathogen Interactions; Humans; Immunity, Innate; Polymorphism, Genetic; Protein Isoforms; Virus Diseases; Virus Replication
PubMed: 34372572
DOI: 10.3390/v13071366 -
Viruses May 2020Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is... (Review)
Review
Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is continuously evolving to expand the repertoire of restriction factors and one such family of intrinsic restriction factors is the APOBEC3 (A3) family of cytidine deaminases. The coordinated expression of seven members of the A3 family of cytidine deaminases provides intrinsic immunity against numerous foreign infectious agents and protects the host from exogenous retroviruses and endogenous retroelements. Four members of the A3 proteins-A3G, A3F, A3H, and A3D-restrict HIV-1 in the absence of virion infectivity factor (Vif); their incorporation into progeny virions is a prerequisite for cytidine deaminase-dependent and -independent activities that inhibit viral replication in the host target cell. HIV-1 encodes Vif, an accessory protein that antagonizes A3 proteins by targeting them for polyubiquitination and subsequent proteasomal degradation in the virus producing cells. In this review, we summarize our current understanding of the role of human A3 proteins as barriers against HIV-1 infection, how Vif overcomes their antiviral activity, and highlight recent structural and functional insights into A3-mediated restriction of lentiviruses.
Topics: APOBEC Deaminases; Animals; Base Sequence; Humans; Lentivirus; Lentivirus Infections; Protein Structure, Tertiary; Structure-Activity Relationship
PubMed: 32471198
DOI: 10.3390/v12060587 -
Viruses Aug 2021The apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) enzyme family in humans has 11 members with diverse functions in metabolism and immunity [...].
The apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) enzyme family in humans has 11 members with diverse functions in metabolism and immunity [...].
Topics: APOBEC-1 Deaminase; Animals; DNA Viruses; Humans; Immunity, Innate; Mice; RNA Editing
PubMed: 34452478
DOI: 10.3390/v13081613 -
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 -
Viruses Mar 2021Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and... (Review)
Review
Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zookeepers. Various FVs are endemic in numerous mammalian natural hosts, such as primates, felines, bovines, and equines, and other animals, but not in humans. They are apathogenic, and significant differences exist between the viral life cycles of FV and other retroviruses. Importantly, FVs replicate in the presence of many well-defined retroviral restriction factors such as TRIM5α, BST2 (Tetherin), MX2, and APOBEC3 (A3). While the interaction of A3s with HIV-1 is well studied, the escape mechanisms of FVs from restriction by A3 is much less explored. Here we review the current knowledge of FV biology, host restriction factors, and FV-host interactions with an emphasis on the consequences of FV regulatory protein Bet binding to A3s and outline crucial open questions for future studies.
Topics: APOBEC Deaminases; Animals; Cell Line; Host Microbial Interactions; Humans; Mutation; Primates; Retroviridae Infections; Retroviridae Proteins; Spumavirus
PubMed: 33803830
DOI: 10.3390/v13030504 -
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