Caretakers and gatekeepers

Cellular gatekeepers include the proteins that regulate cell-cycle progression in response to DNA damage, whereas DNA repair pathways function as genomic caretakers. The p53 and ATM (ataxia-telangiectasia-mutated) proteins behave as cellular gatekeepers, while the non-homologous end-joining (NHEJ) DNA repair machinery acts as a genomic caretaker. NHEJ factors include Ku70, Ku80 and the DNA-PK enzyme, plus XXRC4 and DNA Ligase IV (Lig4), which function in ligation. In the March 13 Proceedings of the National Academy of Science, Sekiguchi et al. report that mutation of the ATM gene rescues the embryonic lethality and neuronal apoptosis associated with Lig4 deficiency in mice (Proc Natl Acad Sci USA 2001, 98:591-596). ATM deficiency failed to relieve defects in lymphocyte development due to the absence of Lig4. These results are similar to observations in Lig4-/-p53-/-mice. ATM deficiency also increased the genome instability, senescence and growth defects of Lig4-deficient fibroblasts. Surprisingly, Sekiguchi et al. report that deletion of ATM caused early embryonic lethality when combined with mutations in Ku or DNA-PK genes. They conclude that the DNA-PK holoenzyme must have an additional NHEJ-independent function.