The DNA damage checkpoint is composed of a group of proteins that sense DNA damage and induce either cell cycle arrest and DNA repair (which mends the damage) or programmed cell death (which removes the damaged cell). Although many cancer cells are checkpoint-defective, efforts to show that mammalian cells with defects in the DNA damage checkpoint are mutating spontaneously have produced controversial results. In addition, it is unclear which DNA damage checkpoint protein physically binds to damaged DNA. We have been addressing both of these issues using the nematode C. elegans . Three C. elegans DNA damage checkpoint mutants have been identified to date:
mrt-2 (
e2663) ,
op241 , and
rad-5 (
mn159) (1,2). The rates and nature of spontaneous mutation in these mutants have been examined using a variety of tests. We find that all of these DNA damage checkpoint mutants display a spontanaeous mutator phenotype, and that most of these spontaneous mutations are deletions. Although
mrt-2 (
e2663) and
op241 mutate at all loci tested,
rad-5 (
mn159) is mutating primarily at a single locus. This surprising result agrees with the observation that
rad-5 (
mn159) is Temperature-sensitive and is therefore unlikely to be a null allele (3). Since
rad-5 (
mn159) is mutating mostly at a single locus,
rad-5 (
mn159) may be defective in sensing a particular kind of spontaneous DNA damage that occurs at this locus. Thus, the RAD-5 checkpoint protein may be a primary 'sensor' of DNA damage, a protein whose identity has eluded the DNA damage checkpoint community for many years. 1. Gartner, A, Milstein, S, Ahmed, S, Hodgkin, J, and Hengartner, MO (2000). A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans . Molecular Cell 5: 435-443. 2. Ahmed, S, and Hodgkin, J (2000). MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans . Nature 403: 159-164. 3. Hartman, PS and Herman RK (1982). Radiation-sensitive mutants of C. elegans . Genetics 102: 159-178.