Distinct and Opposite Activities of Human Terminal Deoxynucleotidyltransferase Splice Variants

Abstract

Evidence for potential human TdT (hTdT) isoforms derived from hTdT genomic sequences led us to identify the short isoform (hTdTS), as well as mature long transcripts containing exon XII (hTdTL1) and another including exon VII (hTdTL2) in lymphoid cells. Normal B and T lymphocytes express exclusively hTdTS and hTdTL2, whereas hTdTL1 expression appears to be restricted to transformed lymphoid cell lines. In in vitro recombination and primer assays, both long isoforms were shown to have 3′→5′ exonuclease activity. Overexpression of hTdTS or hTdTL2 greatly reduced the efficiency of recombination, which was reverted to normal levels by the simultaneous expression of both enzymes. Therefore, alternative splicing may prevent the adverse effects of unchecked elongation or diminution of coding ends during V(D)J recombination, thus affecting the survival of a B or T cell precursor during receptor gene rearrangements. Finally, the newly discovered hTdT isoforms should be considered in future screening of human leukemias.

Nonoverlapping Functions of DNA Polymerases Mu, Lambda, and Terminal Deoxynucleotidyltransferase during Immunoglobulin V(D)J Recombination In Vivo

“…20 amino acids are inserted between the last two exons (Doyen et al, 1993). This insertion has been proposed to allow three distant motifs of the protein to assemble as a new catalytic site, conferring exonuclease activity to the TdTL isoform (Thai et al, 2002;Thai and Kearney, 2004). This TdTL variant, expressed up to the pre-B cell stage, could either process light chain coding extremities or counterbalance the activity of TdT to restrict the length of N additions.…”

MondoA is highly overexpressed in acute lymphoblastic leukemia cells and modulates their metabolism, differentiation and survival

“…DNTT (terminal deoxynucleotidyltransterase) is expressed in normal and malignant pre-B and pre-T lymphocytes during early differentiation and contributes to the generation of antigen-receptor diversity [43]. In addition, DNTT has a strong anti-apoptotic function as its overexpression may contribute to resistance of leukemia cells to thiopurine-based chemotherapeutics [32].…”

Introducing Protein Intrinsic Disorder

“…255,256 For humans and other mammals, multiple proteins are often produced from a single gene, and 40 -60% the genes yield proteins via AS. [257][258][259][260] It was hypothesized that AS very likely provides an important mechanism for enhancing protein diversity in multicellular eukaryotes, 261 playing a crucial role in regulation of protein-protein interactions, ligand binding, and enzymatic activity, [262][263][264][265] and yielding protein isoforms with different, even opposing, functions.…”