active throughout the cell cycle, but is most important during G1 when no homologous template for recombination is available. This regulation is accomplished by the cyclin-dependent kinase Cdk1 (Cdc28 in yeast), which is turned off in G1 and expressed in S and G2. Cdk1 phosphorylates the nuclease Sae2, allowing resection to initiate. V(D)J recombination NHEJ plays a critical role in V(D)J recombination, the process by which B-cell and T-cell receptor diversity is generated in the vertebrate immune system. In V(D)J recombination, hairpin-capped double-strand breaks are created by the RAG1/RAG2 nuclease, which cleaves the DNA at recombination signal sequences. These hairpins are then opened by the Artemis nuclease and joined by NHEJ. A specialized DNA polymerase called terminal deoxynucleotidyl transferase (TdT), which is only expressed in lymph tissue, adds nontemplated nucleotides to the ends before the break is joined. This process couples "variable" (V), "diversity" (D), and "joining" (J) regions, which when assembled together create the variable region of a B-cell or T-cell receptor gene. Unlike typical cellular NHEJ, in which accurate repair is the most favorable outcome, error-prone repair in V(D)J recombination is beneficial in that it maximizes diversity in the coding sequence of these genes. Patients with mutations in NHEJ genes are unable to produce functional B cells and T cells and suffer from severe combined immunodeficiency (SCID). At telomeres Telomeres are normally protected by a "cap" that prevents them from being recognized as double-strand breaks. Loss of capping proteins causes telomere shortening and inappropriate joining by NHEJ, producing dicentric chromosomes which are then pulled apart during mitosis. Paradoxically, some NHEJ proteins are involved in telomere capping. For example, Ku localizes to telomeres and its deletion leads to shortened telomeres. Ku is also required for subtelomeric silencing, the process by which genes located near telomeres are turned off. Consequences of dysfunction Several human syndromes are associated with dysfunctional NHEJ. Hypomorphic mutations in LIG4 and XLF cause LIG4 syndrome and XLF-SCID, respectively. These syndromes share many features including cellular radiosensitivity, microcephaly and severe combined immunodeficiency (SCID) due to defective V(D)J recombination. Loss-of-function mutations in Artemis also cause SCID, but these patients do not show the neurological defects associated with LIG4 or XLF mutations. The difference in severity may be explained by the roles of the mutated proteins. Artemis is a nuclease and is thought to be required only for repair of DSBs with damaged ends, whereas DNA Ligase IV and