Insights into two modes of TdT action in human V(D)J recombination

Terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase expressed in pre-B and pre-T cells that functions in V(D)J recombination to add random nucleotides in a template-independent (TI) mode at junctions between antigen receptor gene segments. However, cellular, biochemical, and structural studies have also revealed a significant, short-length, template-dependent (TD) mode of TdT, in which it takes instructions from a template strand across a double-strand break. Here, we propose that this can occur through an intrachain fold-back synthesis to generate the short inverted repeats at V(D)J recombination junctions observed in early human lymphoid cells and within the adult human antigen receptor repertoire. This duality is also relevant to the functional and structural flexibility observed during the DNA repair process known as nonhomologous DNA end joining (NHEJ).