In bacteria and yeast, many of the genes important in the cellular responses to DNA damage are induced by such damage. The focus of this project is the study of similar processes in mammalian cells and the role of DNA-damage responses in determining the cellular sensitivity to cytotoxic agents, such as used in cancer therapy. Using specialized cloning procedures which we developed, cDNA clones for more than 20 novel DNA-damage-inducible (DDI) genes have been isolated and sequenced. In both bacteria and eukaryotes, one effect of DNA damage is the transient inhibition of DNA synthesis and cell growth; such delays can have a protective effect since mutants lacking growth arrest responses are hypersensitive to certain DNA-damaging agents. We have found that 5 of our clones encode 5 different hamster genes that are coordinately induced either by DNA-damaging agents or by other cell treatments that induce growth arrest such as serum reduction; these genes have been designated gadd (growth arrest- and DNA damage-inducible). In collaboration with D. Nebert and N. Holbrook, we now have good evidence that the gadd genes are coordinately regulated. Two of the gadd genes have been sequenced and newly-described regulatory regions have been identified and partially characterized. Antibodies to one of the proteins have been developed in collaboration with N. Holbrook. Further efforts will focus on the regulation of the DDI genes and their functions.
