Genomic Rearrangements

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Why genomic rearrangements are important for lymphocyte function.

Through a series of steps called the immune response, the body’s immune system attacks invading disease-causing organisms and substances. The cells involved in this immune response are called leukocytes. Leukocytes are produced and stored in the thymus, spleen, and bone marrow (lymphoid organs). There is also lymphoid tissue throughout the body that houses leukocytes (lymph nodes). The leukocytes circulate through the body between the organs and nodes via lymphatic vessels and blood vessels. Lymphocytes are a type of leukocyte. The two kinds of lymphocytes are B lymphocytes and T lymphocytes. Lymphocytes either mature in the bone marrow and become B cells, or they move to the thymus gland and mature in to T cells. Each lymphocyte produces its own specific receptor, an immunoglobulin, which is structurally organized so that it responds to a different antigen. After a cell encounters an antigen that it recognizes it is stimulated to multiply. Antigens are highly varied - to be able to respond to them, the immunoglobulins must be equally diverse.

V(D)J Recombination
To accommodate the diversity of immunoglobulins needed in the human body, the genome would have to be excessively large. Therefore the diversity occurs during the development of B and T lymphocytes via recombination instead. Variability in the epitope binding potential of the receptors is achieved by varying the combination of pre-existing genes known as Variable (V), Diversity (D) and Joining (J) segments, during V(D)J recombination. Figure 1.1 - Location and products of V(D)J recombination ( Figure 1.2 shows the phases of V(D)J recombination and the formation of a new coding joint and discarded signal joint.

Figure 1.2 – V(D)J Recombination (MUTAGENETIX Owen M. Siggs, Eva Marie Y. Moresco, Beutler B)

Gene segments that can be recombined have specific sequence motifs adjacent to them called recombination signal sequence or RSS. A complex containing the products of the recombination activator genes RAG 1 and RAG 2, binds specifically to the RSS motif, flanking two gene segments e.g. V and J, seen in phase 1 of figure 1.2.The individual gene segments, to whose flanking RSS motifs the RAG proteins bind, are selected at random from a number of copies present at each gene locus. The RAG protein complexes bring together the gene segments to be recombined and cleave the DNA exactly at the junction of the gene segment and its adjoining RSS motif. The cleavage creates a hairpin of DNA at the end of the gene segments and double stranded breaks at the ends of the RSS motifs. Additional proteins; DNA dependent protein kinase, Ku, Artemis and a dimer of DNA ligase/XRCC4 are incorporated into a large complex with the RAG proteins. These proteins are the factors that make up the NHEJ pathway which is what joins RAG-dependent double stranded DNA breaks. The next step of V(D)J recombination is the joining of the RSS ends, forming what is called the signal joint, which creates a closed circuit of DNA that serves no further purpose in the recombination process. The DNA hairpins at the ends of the gene segments are then cleaved. An additional enzyme, terminal deoxynuclotidyltransferase or TdT, is recruited and adds additional nucleotides to the ends of the DNA strands. The other enzymes in the complex ligate together the two ends of the gene segments to complete the recombination process. When V(D)J Recombination doesn’t work

Multiple tests have been carried out on mice to establish the importance of the factors that make up the NHEJ pathway and how our bodies would cope if one or a number of these factors weren’t present. Mice deficient in either DNA protein kinase or Artemis were found to exhibit a severe combined immune deficiency. Severe combined immune deficiency is a primary immune deficiency which usually results in the onset of one or more serious infections...
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