Class-switch Recombination Interplay Of Transcription Dna Deamination And Dna Repair Pdf
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- The role of activation-induced deaminase in antibody diversification and genomic instability
- Regulation of AID, the B-cell genome mutator
- Erratum: Class-switch recombination: interplay of transcription, DNA deamination and DNA repair
The role of activation-induced deaminase in antibody diversification and genomic instability
Given that AID can instigate DNA lesions and genomic instability, stringent checks are imposed that constrain and restrict its mutagenic potential. In this review, we will discuss how AID expression and substrate specificity and activity is rigorously enforced at the transcriptional, post-transcriptional, post-translational, and epigenetic levels, and how the DNA-damage response is choreographed with precision to permit targeted activity while limiting bystander catastrophe. B cells are specialized lymphocytes that express Ig receptors or antibodies on their cell surface. A salient feature of B-lymphocytes is their ability to recognize an almost infinite array of antigens. This enormous diversity is achieved through V D J recombination, a process that assembles the exons encoding the amino-terminal variable regions of IgH and IgL from component variable V , diversity D , and joining J segments 1. In the context of specialized structures called germinal centers in secondary lymphoid organs such as the spleen and lymph nodes, mature B cells interact with antigens and undergo class-switch recombination CSR 2 , 3. End-joining of DSBs between two S regions results in the excision of the intervening sequence and juxtaposition of a new set of constant region exons directly downstream of the rearranged V D J segment, thereby generating Ig molecules with the same antigen specificity but with new effector functions 2 , 3 Figure 1.
The mechanisms by which B cells somatically engineer their genomes to generate the vast diversity of antibodies required to challenge the nearly infinite number of antigens that immune systems encounter are of tremendous clinical and academic interest. Recent discoveries indicate a significant promiscuous targeting of this B-cell mutator enzyme genome-wide. Here we discuss the various regulatory elements that control AID activity and prevent AID from inducing genomic instability and thereby initiating oncogenesis. Detection of antigens by the mammalian immune system triggers a two-pronged response, originating in both the adaptive and the innate system wings. The adaptive immune response, which we consider in greater detail in this review, consists of two types of antigen-responsive cells: B and T cells. Secreting antibodies and cytokines, respectively, these antigen-responsive cells recruit macrophages, neutrophils, mast cells, basophils, eosinophils, and natural killer cells to participate in the immune response. These latter six cell types all derive from the pluripotent hematopoietic stem cell HSC , a common precursor found in the bone marrow for a flowchart of lymphocyte development, see Fig.
Regulation of AID, the B-cell genome mutator
DNA lesions inflicted by activation-induced deaminase AID instrumentally initiate the processes reshaping immunoglobulin genes in mature B-cells, from local somatic hypermutation SHM to junctions of distant breaks during class switch recombination CSR. Class switching allows B lymphocytes to replace expression of immunoglobin M with that of immunoglobulins G, A or E. The genetic support of class switching, is a unique and large deletion uniquely occuring within the immunoglobulin heavy chain IgH locus. In immunoglobulin light chain loci, AID only stimulates somatic hypermutation. This study identifies the minimal elements necessary for class-switch recombination to occur instead of hypermutation in a locus targeted by AID, i. PLoS Genet 17 2 : e This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Erratum: Class-switch recombination: interplay of transcription, DNA deamination and DNA repair
J Exp Med 11 May ; 5 : — Class switch recombination CSR allows the humoral immune response to exploit different effector pathways through specific secondary antibody isotypes. However, the molecular mechanisms and factors that control immunoglobulin Ig isotype choice for CSR are unclear. Thus, our results reveal transcriptional competition between constant region genes in individual cells to be a critical and general mechanism for isotype specification during CSR.
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Adaptive immune responses require the generation of a diverse repertoire of immunoglobulins Igs that can recognize and neutralize a seemingly infinite number of antigens. Within the Ig locus, DNA repair pathways are diverted from their canonical role in maintaining genomic integrity to permit AID-directed mutation and deletion of gene coding segments. Recently identified proteins, genes, and regulatory networks have provided new insights into the temporally and spatially coordinated molecular interactions that control the formation and repair of DSBs within the Ig locus. Unravelling the genetic program that allows B cells to selectively alter the Ig coding regions while protecting non-Ig genes from DNA damage advances our understanding of the molecular processes that maintain genomic integrity as well as humoral immunity. Mammalian adaptive immune responses require B cells to produce immunoglobulins Igs , commonly known as antibodies, that can recognize a seemingly infinite number of antigens on foreign pathogens.
Since then, tremendous progress has been achieved toward elucidating how AID functions.
Под визг покрышек, в снопе искр Беккер резко свернул вправо и съехал с дороги. Колеса мотоцикла подпрыгнули, ударившись о бетонное ограждение, так что он едва сумел сохранить равновесие. Из-под колес взметнулся гравий.
Не успел он приняться за чтение отчета службы безопасности, как его мысли были прерваны шумом голосов из соседней комнаты. Бринкерхофф отложил бумагу и подошел к двери. В приемной было темно, свет проникал только сквозь приоткрытую дверь кабинета Мидж.
Стратмор попытался их удержать, но не сумел.