[Cell death and genetic alterations induced by thymidylate stress]

Thymidylate synthase-negative mutants of mouse FM3A cells are immediately committed to cell death upon thymidine starvation. Thymineless death can be mimicked by use of drugs that block the formation of reduced folate or dTMP. In parallel with this thymineless death, DNA double strand breaks and chromosome aberrations are induced. Thymidylate starvation does not induce mutation, whereas very mild thymidylate starvation does. Thymidylate starvation, however, induces strongly a deletion of a heterologous genetic marker at specific sites which is stably integrated in a mouse cell chromosome by means of DNA-mediated gene transfer.