XLF are required for all NHEJ events. Mutations in genes that participate in non-homologous end joining lead to ataxia-telangiectasia (ATM gene), Fanconi anemia (multiple genes), as well as hereditary breast and ovarian cancers (BRCA1 gene). Many NHEJ genes have been knocked out in mice. Deletion of XRCC4 or LIG4 causes embryonic lethality in mice, indicating that NHEJ is essential for viability in mammals. In contrast, mice lacking Ku or DNA-PKcs are viable, probably because low levels of end joining can still occur in the absence of these components. All NHEJ mutant mice show a SCID phenotype, sensitivity to ionizing radiation, and neuronal apoptosis. Aging A system was developed for measuring NHEJ efficiency in the mouse. NHEJ efficiency could be compared across tissues of the same mouse and in mice of different age. Efficiency was higher in the skin, lung and kidney fibroblasts, and lower in heart fibroblasts and brain astrocytes. Furthermore, NHEJ efficiency declined with age. The decline was 1.8 to 3.8-fold, depending on the tissue, in the 5-month-old compared to the 24-month-old mice. Reduced capability for NHEJ can lead to an increase in the number of unrepaired or faultily repaired DNA double-strand breaks that may then contribute to aging. (Also see DNA damage theory of aging.) An analysis of the level of NHEJ protein Ku80 in human, cow, and mouse indicated that Ku80 levels vary dramatically between species, and that these levels are strongly correlated with species longevity. List of proteins involved in NHEJ in human cells Ku70/80 DNA-PKcs DNA Ligase IV XRCC4 XLF Artemis DNA polymerase mu DNA polymerase lambda PNKP Aprataxin APLF BRCA1 BRCA2 CYREN References DNA repair Telomeres