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Nature Aug 2023Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified,...
Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.
Topics: Humans; Cytidine Deaminase; DNA Breaks, Double-Stranded; Genomic Instability; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Drug Resistance, Neoplasm
PubMed: 37407818
DOI: 10.1038/s41586-023-06303-1 -
Nature Genetics Nov 2022Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC)3 cytosine deaminase activity have been found in over half... (Review)
Review
Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC)3 cytosine deaminase activity have been found in over half of cancer types, including some therapy-resistant and metastatic tumors. Driver mutations can occur in APOBEC3-favored sequence contexts, suggesting that mutagenesis by APOBEC3 enzymes may drive cancer evolution. The APOBEC3-mediated signatures are often detected in subclonal branches of tumor phylogenies and are acquired in cancer cell lines over long periods of time, indicating that APOBEC3 mutagenesis can be ongoing in cancer. Collectively, these and other observations have led to the proposal that APOBEC3 mutagenesis represents a disease-modifying process that could be inhibited to limit tumor heterogeneity, metastasis and drug resistance. However, critical aspects of APOBEC3 biology in cancer and in healthy tissues have not been clearly defined, limiting well-grounded predictions regarding the benefits of inhibiting APOBEC3 mutagenesis in different settings in cancer. We discuss the relevant mechanistic gaps and strategies to address them to investigate whether inhibiting APOBEC3 mutagenesis may confer clinical benefits in cancer.
Topics: Humans; Mutagenesis; Neoplasms; APOBEC-1 Deaminase; Mutation; Cytidine Deaminase; APOBEC Deaminases
PubMed: 36280735
DOI: 10.1038/s41588-022-01196-8 -
Frontiers in Immunology 2022Activation induced cytidine deaminase (AID) protein is a member of APOBEC family. AID converts cytidine to uracil, which is a key step for somatic hypermutation (SHM)... (Review)
Review
Activation induced cytidine deaminase (AID) protein is a member of APOBEC family. AID converts cytidine to uracil, which is a key step for somatic hypermutation (SHM) and class switch recombination (CSR). AID also plays critical roles in B cell precursor stages, removing polyreactive B cells from immune repertoire. Since the main function of AID is inducing point mutations, dysregulation can lead to increased mutation load, translocations, disturbed genomic integrity, and lymphomagenesis. As such, expression of AID as well as its function is controlled strictly at various molecular steps. Other members of the APOBEC family also play crucial roles during carcinogenesis. Considering all these functions, AID represents a bridge, linking chronic inflammation to carcinogenesis and immune deficiencies to autoimmune manifestations.
Topics: Humans; Somatic Hypermutation, Immunoglobulin; Cytidine Deaminase; Friends; Immunoglobulin Class Switching; Carcinogenesis
PubMed: 36405752
DOI: 10.3389/fimmu.2022.965312 -
Virology May 2015The APOBEC family of single-stranded DNA cytosine deaminases comprises a formidable arm of the vertebrate innate immune system. Pre-vertebrates express a single APOBEC,... (Review)
Review
The APOBEC family of single-stranded DNA cytosine deaminases comprises a formidable arm of the vertebrate innate immune system. Pre-vertebrates express a single APOBEC, whereas some mammals produce as many as 11 enzymes. The APOBEC3 subfamily displays both copy number variation and polymorphisms, consistent with ongoing pathogenic pressures. These enzymes restrict the replication of many DNA-based parasites, such as exogenous viruses and endogenous transposable elements. APOBEC1 and activation-induced cytosine deaminase (AID) have specialized functions in RNA editing and antibody gene diversification, respectively, whereas APOBEC2 and APOBEC4 appear to have different functions. Nevertheless, the APOBEC family protects against both periodic viral zoonoses as well as exogenous and endogenous parasite replication. This review highlights viral pathogens that are restricted by APOBEC enzymes, but manage to escape through unique mechanisms. The sensitivity of viruses that lack counterdefense measures highlights the need to develop APOBEC-enabling small molecules as a new class of anti-viral drugs.
Topics: Animals; Cytidine Deaminase; DNA Viruses; Host-Pathogen Interactions; Humans; Multigene Family; RNA, Viral; Retroviridae; Vertebrates
PubMed: 25818029
DOI: 10.1016/j.virol.2015.03.012 -
Molecular Cell May 2013Chemical modifications to the DNA and histone protein components of chromatin can modulate gene expression and genome stability. Understanding the physiological impact... (Review)
Review
Chemical modifications to the DNA and histone protein components of chromatin can modulate gene expression and genome stability. Understanding the physiological impact of changes in chromatin structure remains an important question in biology. As one example, in order to generate antibody diversity with somatic hypermutation and class switch recombination, chromatin must be made accessible for activation-induced cytidine deaminase (AID)-mediated deamination of cytosines in DNA. These lesions are recognized and removed by various DNA repair pathways but, if not handled properly, can lead to formation of oncogenic chromosomal translocations. In this review, we focus the discussion on how chromatin-modifying activities and -binding proteins contribute to the native chromatin environment in which AID-induced DNA damage is targeted and repaired. Outstanding questions remain regarding the direct roles of histone posttranslational modifications and the significance of AID function outside of antibody diversity.
Topics: Animals; Chromatin; Cytidine Deaminase; DNA; DNA Damage; DNA Repair; Humans
PubMed: 23664375
DOI: 10.1016/j.molcel.2013.04.017 -
Organic & Biomolecular Chemistry Jul 2021The tolerance of cytidine deaminase (CDA) to expanded heterocycles is explored via three fluorescent cytidine analogues, where the pyrimidine core is fused to three...
The tolerance of cytidine deaminase (CDA) to expanded heterocycles is explored via three fluorescent cytidine analogues, where the pyrimidine core is fused to three distinct five-membered heterocycles at the 5/6 positions. The reaction between CDA and each analogue is followed by absorption and emission spectroscopy, revealing shorter reaction times for all analogues than the native substrate. Pseudo-first order and Michaelis-Menten kinetic analyses provide insight into the enzymatic deamination reactions and assist in drawing comparison to established structure activity relationships. Finally, inhibitor screening modalities are created for each analogue and validated with zebularine and tetrahydrouridine, two known CDA inhibitors.
Topics: Cytidine Deaminase
PubMed: 34019616
DOI: 10.1039/d1ob00705j -
Cellular and Molecular Life Sciences :... Aug 2022Identifying new molecular targets for novel anticancer treatments is a major challenge in clinical cancer research. We have shown that cytidine deaminase (CDA)...
Identifying new molecular targets for novel anticancer treatments is a major challenge in clinical cancer research. We have shown that cytidine deaminase (CDA) expression is downregulated in about 60% of cancer cells and tissues. In this study, we aimed to develop a new anticancer treatment specifically inhibiting the growth of CDA-deficient tumor cells. High-throughput screening of a chemical library led to the identification of a naphthol derivative, X55, targeting CDA-deficient tumor cells preferentially, without affecting the growth of non-tumoral cells regardless of CDA expression status. Metabolomic profiling revealed that CDA-deficient HeLa cells differed markedly from control HeLa cells. X55 treatment had a moderate effect on control cells, but greatly disturbed the metabolome of CDA-deficient HeLa cells, worsening the deregulation of many metabolites. In particular, the levels of the three oncometabolites, fumarate, succinate and 2-hydroxyglutarate, were significantly lower in CDA-depleted cells, and this decrease in levels was exacerbated by X55 treatment, revealing an unexpected link between CDA deficiency, mitochondrial function and X55 response. Finally, we identified strong downregulation of MAPT (encoding Tau, a microtubule associated protein) expression as a reliable predictive marker for tumor cell X55 sensitivity.
Topics: Cytidine Deaminase; HeLa Cells; Humans; Naphthols
PubMed: 35925417
DOI: 10.1007/s00018-022-04487-9 -
Acta Biochimica Et Biophysica Sinica May 2022Activation-induced cytidine deaminase (AID) initiates somatic hypermutation of immunoglobulin (Ig) gene variable regions and class switch recombination (CSR) of Ig heavy... (Review)
Review
Activation-induced cytidine deaminase (AID) initiates somatic hypermutation of immunoglobulin (Ig) gene variable regions and class switch recombination (CSR) of Ig heavy chain constant regions. Two decades of intensive research has greatly expanded our knowledge of how AID functions in peripheral B cells to optimize antibody responses against infections, while maintaining tight regulation of AID to restrain its activity to protect B cell genomic integrity. The many exciting recent advances in the field include: 1) the first description of AID's molecular structure, 2) remarkable advances in high throughput approaches that precisely track AID targeting genome-wide, and 3) the discovery that the cohesion-mediate loop extrusion mechanism [initially discovered in V(D)J recombination studies] also governs AID-medicated CSR. These advances have significantly advanced our understanding of AID's biochemical properties and AID's function and regulation . This mini review will discuss these recent discoveries and outline the challenges and questions that remain to be addressed.
Topics: B-Lymphocytes; Cytidine Deaminase; Immunoglobulin Class Switching; Somatic Hypermutation, Immunoglobulin
PubMed: 35975606
DOI: 10.3724/abbs.2022070 -
Current Opinion in Immunology Aug 2020The adaptive immune systems of all vertebrates rely on self-DNA mutating enzymes to assemble their antigen receptors in lymphocytes of their two principal lineages. In... (Review)
Review
The adaptive immune systems of all vertebrates rely on self-DNA mutating enzymes to assemble their antigen receptors in lymphocytes of their two principal lineages. In jawed vertebrates, the RAG1/2 recombinase directs V(D)J recombination of B cell and T cell receptor genes, whereas the activation-induced cytidine deaminase AID engages in their secondary modification. The recombination activating genes (RAG) 1 and 2 evolved from an ancient transposon-encoded genome modifier into a self-DNA mutator serving adaptive immunity; this was possible as a result of domestication, involving several changes in RAG1 and RAG2 proteins suppressing transposition and instead facilitating-coupled cleavage and recombination. By contrast, recent evidence supports the notion that the antigen receptors of T-like and B-like cells of jawless vertebrates, designated variable lymphocyte receptors (VLRs), are somatically assembled through a process akin to gene conversion that is believed to be dependent on the activities of distant relatives of AID, the cytidine deaminases CDA1 and CDA2, respectively. It appears, therefore, that the precursors of AID and CDAs underwent a domestication process that changed their target range from foreign nucleic acids to self-DNA; this multi-step evolutionary process ensured that the threat to host genome integrity was minimized. Here, we review recent findings illuminating the evolutionary steps associated with the domestication of the two groups of genome editors, RAG1/2 and cytidine deaminases, indicating how they became the driving forces underlying the emergence of vertebrate adaptive immune systems.
Topics: Adaptive Immunity; Animals; Cytidine Deaminase; DNA-Binding Proteins; Gene Editing; Humans; Vertebrates
PubMed: 32353821
DOI: 10.1016/j.coi.2020.03.001 -
Wiley Interdisciplinary Reviews.... 2010RNA editing defines a molecular process by which a nucleotide sequence is modified in the RNA transcript and results in an amino acid change in the recoded message from... (Review)
Review
RNA editing defines a molecular process by which a nucleotide sequence is modified in the RNA transcript and results in an amino acid change in the recoded message from that specified in the gene. We will restrict our attention to the type of RNA editing peculiar to mammals, i.e., nuclear C to U RNA editing. This category of RNA editing contrasts with RNA modifications described in plants, i.e., organellar RNA editing (reviewed in Ref 1). Mammalian RNA editing is genetically and biochemically classified into two groups, namely insertion-deletional and substitutional. Substitutional RNA editing is exclusive to mammals, again with two types reported, namely adenosine to inosine and cytosine to uracil (C to U). This review will examine mammalian C to U RNA editing of apolipoproteinB (apoB) RNA and the role of the catalytic deaminase Apobec-1. We will speculate on the functions of Apobec-1 beyond C to U RNA editing as implied from its ability to bind AU-rich RNAs and discuss evidence that dysregulation of Apobec-1 expression might be associated with carcinogenesis through aberrant RNA editing or altered RNA stability.
Topics: APOBEC-1 Deaminase; Animals; Cell Compartmentation; Cytidine Deaminase; Heterogeneous-Nuclear Ribonucleoproteins; Humans; Mammals; Mice; Mice, Knockout; Mice, Transgenic; Models, Biological; Phenotype; RNA Editing; RNA Stability; RNA-Binding Proteins; Systems Biology
PubMed: 20836050
DOI: 10.1002/wsbm.82