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Cancer Letters Jan 2021Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition,... (Review)
Review
Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition, numerous other genetic and epigenetic factors also are involved in the underlying pathogenesis of cervical cancer. Recently, it has been reported that apolipoprotein B mRNA editing enzyme catalytic polypeptide like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. Particularly, the APOBEC3 family was shown to induce tumor mutations by aberrant DNA editing mechanism. In general, APOBEC3 enzymes play a pivotal role in the deamination of cytidine to uridine in DNA and RNA to control diverse biological processes such as regulation of protein expression, innate immunity, and embryonic development. Innate antiviral activity of the APOBEC3 family members restrict retroviruses, endogenous retro-element, and DNA viruses including the HPV that is the leading risk factor for cervical cancer. This review briefly describes the pathogenesis of cervical cancer and discusses in detail the recent findings on the role of APOBEC in the molecular pathogenesis of cervical cancer.
Topics: APOBEC Deaminases; Animals; Female; Humans; Immunity, Innate; Uterine Cervical Neoplasms
PubMed: 33038491
DOI: 10.1016/j.canlet.2020.10.004 -
Molekuliarnaia Biologiia 2022Proteins of the AID/APOBEC family are capable of cytidine deamination in nucleic acids forming uracil. These enzymes are involved in mRNA editing, protection against... (Review)
Review
Proteins of the AID/APOBEC family are capable of cytidine deamination in nucleic acids forming uracil. These enzymes are involved in mRNA editing, protection against viruses, the introduction of point mutations into DNA during somatic hypermutation, and antibody isotype switching. Since these deaminases, especially AID, are potent mutagens, their expression, activity, and specificity are regulated by several intra-cellular mechanisms. In this review, we discuss the mechanisms of impaired expression and activation of AID/APOBEC proteins in human tumors and their role in carcinogenesis and tumor progression. Also, the diagnostic and potential therapeutic value of increased expression of AID/APOBEC in different types of tumors is analyzed. We assume that in the case of solid tumors, increased expression of endogenous deaminases can serve as a marker of response to immunotherapy since multiple point mutations in host DNA could lead to amino acid substitutions in tumor proteins and thereby increase the frequency of neoepitopes.
Topics: APOBEC Deaminases; Antiviral Restriction Factors; Carcinogenesis; Cytidine Deaminase; Humans; Mutagens
PubMed: 35082258
DOI: 10.31857/S0026898422010086 -
Chromosome Research : An International... Mar 2018Long interspersed element-1 (LINE-1 or L1) retrotransposons represent the only functional family of autonomous transposable elements in humans and formed 17% of our... (Review)
Review
Long interspersed element-1 (LINE-1 or L1) retrotransposons represent the only functional family of autonomous transposable elements in humans and formed 17% of our genome. Even though most of the human L1 sequences are inactive, a limited number of copies per individual retain the ability to mobilize by a process termed retrotransposition. The ongoing L1 retrotransposition may result in insertional mutagenesis that could lead to negative consequences such as genetic disease and cancer. For this reason, cells have evolved several mechanisms of defense to restrict L1 activity. Among them, a critical role for cellular deaminases [activation-induced deaminase (AID)/apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) and adenosine deaminases that act on RNA (ADAR) enzymes] has emerged. The majority of the AID/APOBEC family of proteins are responsible for the deamination of cytosine to uracil (C-to-U editing) within DNA and RNA targets. The ADARs convert adenosine bases to inosines (A-to-I editing) within double-stranded RNA (dsRNA) targets. This review will discuss the current understanding of the regulation of LINE-1 retrotransposition mediated by these enzymes.
Topics: APOBEC Deaminases; Adenosine Deaminase; Cytidine Deaminase; DNA; Humans; Long Interspersed Nucleotide Elements; RNA; RNA, Double-Stranded; Retroelements
PubMed: 29396793
DOI: 10.1007/s10577-018-9572-5 -
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 -
Histology and Histopathology Feb 2018Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) is a family of evolutionarily conserved cytidine deaminases, encoded by eleven genes located in... (Review)
Review
Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) is a family of evolutionarily conserved cytidine deaminases, encoded by eleven genes located in the human genome. APOBECs play key roles in innate immunity through their ability to mutagenize viral DNA and restrict rival replication. Recent cancer genomics revealed APOBEC3 subtype-mediated APOBEC-signature mutations are common in a broad spectrum of human cancers. The pervasive APOBEC3 activation in the host genome which converts cytosine to uracile during RNA editing has been suggested to depend on ATR/chk1 pathways. In this review, we highlight how microRNAs interact with the APOBEC gene family and post-transcriptionally regulate APOBEC gene expression, and we speculate how targeting specific microRNAs may reduce host genome mutagenesis via inactivation of APOBEC deaminases.
Topics: APOBEC Deaminases; Animals; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms
PubMed: 28604942
DOI: 10.14670/HH-11-912 -
Cell Nov 2020The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics"...
The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.
Topics: APOBEC Deaminases; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Carcinogenesis; Cohort Studies; DNA Damage; DNA Repair; Female; Humans; Immunotherapy; Metabolomics; Middle Aged; Molecular Targeted Therapy; Mutagenesis; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Proteogenomics; Receptor, ErbB-2; Retinoblastoma Protein; Tumor Microenvironment
PubMed: 33212010
DOI: 10.1016/j.cell.2020.10.036 -
Medical Science Monitor : International... May 2006The APOBEC (acronym for apolipoprotein B editing catalytic polypeptide) family of cytidine deaminases are widely distributed in the biological world and play a central... (Review)
Review
The APOBEC (acronym for apolipoprotein B editing catalytic polypeptide) family of cytidine deaminases are widely distributed in the biological world and play a central role in diverse enzymatic pathways. Members of this family (APOBEC3G and APOBEC3F) have been recently shown to be able to restrict HIV-1 replication in physiologically relevant target cells (macrophages, lymphocytes), presumably by triggering extensive deamination of the viral RNA/DNA replication intermediates. This natural antiretroviral host defense mechanism is counteracted by the HIV-1 protein Vif, which is able to target APOBECs to degrade. The so-called "Vif/APOBEC3G paradigm" has been confirmed by a growing literature. However, evidence arising from recent studies has expanded this view, showing that the replication of other viruses is also restricted by APOBEC family members and suggesting antiviral mechanism(s) of action unrelated to the catalytic activity of these proteins. Furthermore, evolutionary investigations on primates have shown that APOBEC3 gene expansion might be related to an ancient adaptive selection to prevent endogenous genetic instability, indicating an additional ancient protective role of APOBECs. This article is aimed at broadening the current knowledge about the antiviral activity of the APOBEC members and to highlight the notion that their role(s) might be more general than previously anticipated.
Topics: APOBEC-1 Deaminase; APOBEC-3G Deaminase; Amino Acid Sequence; Animals; Anti-HIV Agents; Cytidine Deaminase; Gene Products, vif; HIV Infections; HIV-1; Humans; In Vitro Techniques; Molecular Sequence Data; Nucleoside Deaminases; Repressor Proteins; Sequence Homology, Amino Acid; Virus Replication; vif Gene Products, Human Immunodeficiency Virus
PubMed: 16641889
DOI: No ID Found -
Science (New York, N.Y.) Nov 2016Tobacco smoking increases the risk of at least 17 classes of human cancer. We analyzed somatic mutations and DNA methylation in 5243 cancers of types for which tobacco...
Tobacco smoking increases the risk of at least 17 classes of human cancer. We analyzed somatic mutations and DNA methylation in 5243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clocklike mutational process. Smoking is associated with limited differences in methylation. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.
Topics: APOBEC Deaminases; Carcinogens; CpG Islands; DNA Damage; DNA Methylation; Exome; Humans; Mutation; Neoplasms; Risk; Smoking; Nicotiana
PubMed: 27811275
DOI: 10.1126/science.aag0299 -
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 -
International Journal of Molecular... Jan 2021Besides smoking and alcohol, human papillomavirus (HPV) is a factor promoting head and neck squamous cell carcinoma (HNSCC). In some human tumors, including HNSCC, a... (Review)
Review
Besides smoking and alcohol, human papillomavirus (HPV) is a factor promoting head and neck squamous cell carcinoma (HNSCC). In some human tumors, including HNSCC, a number of mutations are caused by aberrantly activated DNA-modifying enzymes, such as the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) family of cytidine deaminases. As the enzymatic activity of APOBEC proteins contributes to the innate immune response to viruses, including HPV, the role of APOBEC proteins in HPV-driven head and neck carcinogenesis has recently gained increasing attention. Ongoing research efforts take the cue from two key observations: (1) APOBEC expression depends on HPV infection status in HNSCC; and (2) APOBEC activity plays a major role in HPV-positive HNSCC mutagenesis. This review focuses on recent advances on the role of APOBEC proteins in HPV-positive vs. HPV-negative HNSCC.
Topics: APOBEC Deaminases; Alphapapillomavirus; Carcinogenesis; Head and Neck Neoplasms; Humans; Immunity, Innate; Mutagenesis; Mutation; Papillomavirus Infections; Squamous Cell Carcinoma of Head and Neck
PubMed: 33573337
DOI: 10.3390/ijms22031402