Our goal is to elucidate the structure and molecular mechanisms controlling the expression of terminal deoxynucleotidyl transferase (TdT) during hemopoietic cell differentiation and following neoplastic transformation. TdT is a DNA polymerase that catalyzes polymerization of deoxynucleoside triphosphates without template instruction. Because expression of enzyme activity is restricted to several precursors of lymphocytes and their leukemic counterparts, TdT has been postulated as one source for the generation of somatic mutations and implicated in the deletion of autoreactive lymphocytes. Our overall goal has three principal objectives: (1) elucidation of the structure of the TdT gene in nonexpressing, expressing, and neoplastic cells; (2) determination of mechanisms governing TdT gene expression in normal and neoplastic cells; and (3) determination of the role of posttranslational cleavage and phosphorylation on TdT subcellular localization and enzymatic activity. In addition, an extension of these studies to nonmammalian species will be carried out in order to shed light on the putative correlation between the appearance of the immune system and evolution of the TdT gene. The tools required to pursue these objectives are now available to us. During the current grant period, we constructed and isolated a battery of TdT cDNA probes and monoclonal antibodies upon which our experimental approach is now based. (M)
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