Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis.

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 intracellular 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.

[Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis].

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.

[Body's Own Epitopes among Foreign Ones: T Cells and Autoantigens].

T cells play a key role in adaptive immunity reactions, recognizing antigens using variable TCRs. Functional TCR subunit genes are formed by somatic rearrangement, and some of the resulting TCRs recognize autoantigens, the body's own molecules. The autoreactive T cells that carry such TCRs pose a threat of inducing immune reactions against their own organism. In the course of the immune system's development, some autoreactive T lymphocytes are eliminated by apoptosis, some differentiate into immunosuppressive regulatory T cells, which support immunological tolerance to autoantigens, and the rest fall into a non-functional state of anergy. Suppression of effector T cells by regulatory T cells is mediated by immunosuppressive cytokines and costimulatory molecules, depletion of stimulating IL-2, removal of autoreactive peptides together with MHC molecules, and in other ways. Impairment of self-tolerance leads to autoimmune diseases. However, the loss of immunological tolerance can be employed in tumor treatment, allowing immunotherapy and the use of the potential of autoreactive effector T cells. The fact that the efficacious immunotherapy of tumors is often accompanied by adverse autoimmune reactions currently seems to be the inevitable price paid by using this approach.

[Splicing Pattern of mRNA in Thymus Epithelial Cells Limitsthe Transcriptome Available for Negative Selection of Autoreactive T Cells].

Successful negative selection of autoreactive T cells requires expression of maximum amount of epitopes representing all possible protein isoforms in the thymus. Absence of some possible protein spliceforms in the thymus due to realization of some, but not all splicing combination, may limit the negative selection. Here we show that about 25% of studied mouse genes with well-described alternative splicing event encode some epitopes hidden from thymus. For five out of 10 randomly selected genes with predicted "hidden" epitopes, namely, Add2, Dst, Golga7, Lmna, Nasp, these findings were confirmed experimentally. Thus, for approximately 10-15% of alternatively expressed genes, their splicing patterns in Thymus may limit the set of epitopes available for negative selection.

Possible Mechanisms of Acquisition of Herpesvirus Virokines.

The genomes of certain types of human and primate herpesviruses contain functional homologs of important host cytokines (IL-6, IL-17, and IL-10), or so-called virokines. Virokines can interact with immune cell receptors, transmit a signal to them, and thus switch the type of immune response that facilitates viral infection development. In this work, we have summarized possible ways of virokine origin and proposed an evolutionary scenario of virokine acquisition with involvement of retroviral coinfection of the host. This scenario is probably valid for vIL-6 of HHV-8 and MRV-5 viruses, vIL-17 of HVS virus, and vIL-10 of HHV-4, Bonobo-HV, RhLCV, and BaLCV viruses. The ability to acquire cytokine genes allows herpesviruses to implement unique strategies of avoiding the immune response and provides them an evolutionary advantage: more than 90% of the host population can be chronically infected with different herpesviruses. It is possible that the biological success of herpesviruses can be partially due to their cooperation with another group of viruses. This hypothesis emphasizes the importance of studies on the reciprocal influence of pathogens on their coinfection, as well as their impact on the host organism.

[Evolutionary plasticity of IL-6 cytokine family].

The IL-6 family of cytokines includes a variety of proteins that function not only within the immune system, but also in other organs, tissues, and types of cells, including neurons. The common evolutionary origin of the IL-6 family proteins determines similar mechanisms of reception and intracellular signaling, although their primary structures are highly variable, as well as their biological functions. We have demonstrated that the members of the IL-6 family have high evolutionary plasticity. This manifests in a high degree of population polymorphism for IL-6 family genes, as well as varying degrees of evolutionary conservation among members of the family. The degree of evolutionary conservation of IL-6 family proteins does not correlate with the mechanisms of interaction between these cytokines and their receptors.

[Genetic mechanisms of adaptive immunity emergence in vertebrates].

The adaptive immune system in vertebrates emerged in a multistep process that can be reconstructed on the basis of the data concerning the structure of immune systems of modern cartilaginous and bony fishes, as well as of cyclostomes. The most probable evolutionary scenario is likely to be as follows: the T cell receptor loci emerged on the basis of NK cell-like receptor genes; the antibody loci evolved on the basis of T cell receptor loci; the MHC locus arose on the basis of the locus responsible for innate immunity of early chordates. The ancestral MHC molecules likely participated in the transplantation immunity before they acquired the ability of antigen peptide presentation.

Mouse lymphomyeloid cells can function with significantly decreased expression levels of cytochrome C.

Cytochrome c is an indispensable electron carrier in the mitochondrial respiratory chain and also an important mediator of the internal pathway triggering apoptosis. Mice with a complete deficiency of the Cycs gene encoding the somatic cytochrome c die during the embryogenesis. Using the technology of LoxP-cre-dependent tissue-specific recombination, we obtained some mouse strains with significantly reduced expression of cytochrome c in certain cell types ("conditional genetic knockdown"). This knockdown was achieved by abrogation of the normal splicing of the Cycs locus pre-mRNA due to an additional acceptor site inside the stop-cassette neo(r). Previously, we observed embryonic lethality in homozygous mice with the same knockdown of cytochrome c in all cells of the organism. In the present work we studied two novel mouse strains with conditional knockdown of the Cycs gene in T lymphocytes and macrophages. Somewhat surprisingly, the mice of these two strains under normal conditions were not phenotypically different from the wild-type mice, either on the whole organism level or on the level of activity of individual target cells. Thus, the amount of cytochrome c in lymphomyeloid cells does not affect their development and normal functioning.

[Hyperplastic skin growth on the head of goldfish--comparative oncology aspects].

Dynamics of development and morphology of hyperplastic skin lesions ("hoods") on the head of goldfish, which were bred using artificial selection for more than thousand years, were studied. During monitoring of hundred fishes, at the age of 6 months "hoods" were found in 39.5%, among 14 months-old fishes in 60,7%. Morphologic examination of "hoods" on various stages of development revealed epithelial hyperplasia with increased clear mucous cells number, dermis thickening and oedema. On later stages developed papillomatous outgrowth and areas of epithelial intrusion. The comparative oncology analysis allow to hypothesize these skin growth to be a genetically determined benign neoplasm. This is the first example of artificially selected neoplasm described in the literature. It supports our hypothesis of the possible evolutionary role of tumors.

Cytochrome c: the Achilles' heel in apoptosis.

Cytochrome c is a well-known mitochondrial protein that fulfills life-supporting functions by transferring electrons to the respiratory chain to maintain ATP production. However, during the activation of apoptotic machinery, it is released from mitochondria and, being in the cytosol, it either triggers the activation of the caspase cascade in intrinsic apoptotic pathway, or it is involved in the amplification of extrinsic apoptotic signaling. Accumulating evidence suggests that only unmodified holocytochrome c is efficient in the stimulation of apoptosis. Considering the importance of cytochrome c in both life and death, it was of significant interest to investigate the complete or partial cytochrome c deficiency in vivo. Here, we discuss the importance of distinct amino acid residues for various functions of cytochrome c in cells and mice with targeted cytochrome c mutations.

[Tumor-specific expression of PBOV1, a new gene in evolution].

We identified mRNA of the newly discovered gene PBOV1 in a multitude of samples from tumors of the brain, lung, liver, gallbladder, colon, small intestine, mammary gland, uterus, ovary, ureter, adrenals, parotid, thymus and spleen. However, out of 29 intact adult and 8 fetal tissues, only pancreas was characterized by weak expression of the gene. Our results demonstrated that the PBOV1 gene expression is tumor-specific and has a potential as tumor marker. It is worth mentioning that we had predicted that property on the basis of available evolutionary data.