The topoisomerase-related function gene TRF4 affects cellular sensitivity to the antitumor agent camptothecin

Camptothecin is an antitumor agent that kills cells by converting DNA topoi somerase I into a DNA-damaging poison. Although camptothecin derivatives ar e now being used to treat tumors in a variety of clinical protocols, the ce llular factors that influence sensitivity to the drug are only beginning to be understood. We report here that two genes required for sister chromatid cohesion, TRF4 and MCD1/SCC1, are also required to repair camptothecin-med iated damage to DNA. The hypersensitivity to camptothecin in the trf4 mutan t does not result from elevated expression of DNA topoisomerase I. We show that Trf4 is a nuclear protein whose expression is cell cycle-regulated at a post-transcriptional level. Suppression of camptothecin hypersensitivity in the trf4 mutant by gene overexpression resulted in the isolation of thre e genes: another member of the TRF4 gene family, TRF5, and two genes that m ay influence higher order chromosome structure, ZDS1 and ZDS2, We have isol ated and sequenced two human TRF4 family members, hTRF4-1 and hTRF4-2. The hTRF4-1 gene maps to chromosome 5p15, a region of frequent copy number alte ration in several tumor types. The evolutionary conservation of TRF4 sugges ts that it may also influence mammalian cell sensitivity to camptothecin.