4/27/2023 0 Comments Swat scidaThe CEs require further processing before the joining, by which hairpins are opened, and nucleotides added and/or deleted at the junctions of rearranged products. The resolution of SEs and CEs leads to the direct fusion of the two blunt SEs mostly in a head-to-head fashion, and the joining of two CEs between the V, (D), and J elements to be assembled. Each cleavage results in two blunt signal ends (SE), 4 and two covalently sealed (hairpinned) coding ends (CE). It is well established that the RAG1 and RAG2 (RAG1/2) complex initiates V(D)J recombination in lymphoid cells by recognizing and cleaving at the conserved recombination signal sequences that flank the germline V, (D), and J coding elements. The significance of this process has been well documented by analyses of animal models carrying germline mutations/deletions in genes encoding essential proteins, and also by studies of some rare types of human T −B −NK + SCID caused by defects in genes essential for this process ( 2). Maturation of T and B lymphocytes requires V(D)J recombination in which the exons that encode for V regions of Ig and TCR are assembled from their germline components, V, D, and J gene segments ( 1). Our results suggest that the V(D)J and DNA repair defects seen in this mArt −/− mouse model are comparable to those in humans with Artemis deficiency, and that the recovery of immunity following HSC transplantation favors T rather than B cell reconstitution, consistent with what is seen in children with this form of SCID. Large numbers (40,000) of allogeneic mismatched HSC or pretreatment with 300 cGy of radiation overcame graft resistance, resulting in limited B cell engraftment. Hemopoietic stem cell (HSC) transplantation using 500-5000 enriched congenic, but not allogeneic mismatched HSC corrected the T cell and partially corrected the B cell defect. mArt −/− embryonic fibroblasts show increased sensitivity to ionizing radiation. Artemis-deficient mice show a similar T −B − NK + immunodeficiency phenotype, and carry a profound impairment in coding joint rearrangement, while retaining intact signal ends and close to normal signal joint formation. We have cloned the Artemis murine counterpart, mArt, and generated a mouse with a targeted disruption of mArt. This novel protein has been implicated in DNA double-strand break repair and V(D)J recombination. Artemis is a mammalian protein, the absence of which results in SCID in Athabascan-speaking Native Americans (SCIDA).
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