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Abstract
The repair of chromosome breaks is essential to maintain genome integrity. Both in mammalian cells and in budding yeast, repair in the G1 phase of the cell cycle is particularly dependent on nonhomologous end-joining (NHEJ) to repair broken chromosomes. NHEJ is important in repairing double-strand breaks (DSBs) that arise during both V(D)J recombination and class switch recombination (CSR) events in the immune system. End-joining also is responsible for generating chromosomal translocations that are associated with various cancers. Work by Guirouilh-Barbat et al. (1) published in a recent issue of PNAS and by several other laboratories (2–4) has revealed that–in addition to the “classical” NHEJ pathway–there is a robust alternative pathway that also contributes to the generation of translocations. Our current understanding of the mechanisms of NHEJ results from a dynamic interplay between genetics and biochemistry both in mammals and in budding yeast (for reviews, see refs. 5–7). A major motivation to identify the genes responsible for NHEJ has been the study of end-joinings in both V(D)J recombination and Ig CSR in mammals, driven by the identification of immune-compromised humans. A second impetus has been the identification of genes conferring x-ray resistance. These studies led to the identification of DNA-protein kinase catalytic subunit (PKcs) and the Ku70 and Ku80 proteins, which play a central role both in immune cell recombination and in resistance to ionizing radiation. Further work led to the identification of a number of XRCC genes conferring radio-resistance. Subsequent studies in budding yeast confirmed that Ku proteins were also essential for NHEJ (there is no DNA-PKcs). Research using budding yeast identified other NHEJ components, notably DNA ligase 4, its partner Lif1 (whose mammalian homolog is XRCC4), and Nej1 (whose mammalian homolog is XLF/Cernunnos) † . Ku-deficient mice are viable but severely immunocompromised, whereas mice …