are opened by the activity of Artemis. If they are opened at the center, a blunt DNA end will result; however in many cases, the opening is "off-center" and results in extra bases remaining on one strand (an overhang). These are known as palindromic (P) nucleotides due to the palindromic nature of the sequence produced when DNA repair enzymes resolve the overhang. The process of hairpin opening by Artemis is a crucial step of V(D)J recombination and is defective in the severe combined immunodeficiency (scid) mouse model. Next, XRCC4, Cernunnos, and DNA-PK align the DNA ends and recruit terminal deoxynucleotidyl transferase (TdT), a template-independent DNA polymerase that adds non-templated (N) nucleotides to the coding end. The addition is mostly random, but TdT does exhibit a preference for G/C nucleotides. As with all known DNA polymerases, the TdT adds nucleotides to one strand in a 5' to 3' direction. Lastly, exonucleases can remove bases from the coding ends (including any P or N nucleotides that may have formed). DNA polymerases λ and μ then insert additional nucleotides as needed to make the two ends compatible for joining. This is a stochastic process, therefore any combination of the addition of P and N nucleotides and exonucleolytic removal can occur (or none at all). Finally, the processed coding ends are ligated together by DNA ligase IV. All of these processing events result in a paratope that is highly variable, even when the same gene segments are recombined. V(D)J recombination allows for the generation of immunoglobulins and T cell receptors to antigens that neither the organism nor its ancestor(s) need to have previously encountered, allowing for an adaptive immune response to novel pathogens that develop or to those that frequently change (e.g., seasonal influenza). However, a major caveat to this process is that the DNA sequence must remain in-frame in order to maintain the correct amino acid sequence in the final protein product. If the resulting sequence is out-of-frame, the development of the cell will be arrested, and the cell will not survive to maturity. V(D)J recombination is therefore a very costly process that must be (and is) strictly regulated and controlled. See also B cell receptor T cell receptor Basel Institute for Immunology Charles M. Steinberg NKT cell Recombination-activating gene References Further reading V(D)J Recombination. Series: Advances in Experimental Medicine and Biology, Vol. 650 Ferrier, Pierre (Ed.) Landes Bioscience 2009, XII, 199 p.