INTEGRATION OF SIMIAN VIRUS-40 INTO CELLULAR DNA OCCURS AT OR NEAR TOPOISOMERASE-II CLEAVAGE HOT-SPOTS INDUCED BY VM-26 (TENIPOSIDE)

Inhibition of DNA topoisomerase II in simian virus 40 (SV40)-infected BSC-1 cells with a topoisomerase II poison, VM-26 (teniposide), result ed in rapid conversion of a population of the SV40 DNA into a high-mol ecular-weight form. Characterization of this high-molecular-weight for m of SV40 DNA suggests that it is linear, double stranded, and a recom binant with SV40 DNA sequences covalently joined to cellular DNA. The majority of the integrants contain fewer than two tandem copies of SV4 0 DNA. Neither DNA-damaging agents, such as mitomycin and UV, nor the topoisomerase I inhibitor camptothecin induced detectable integration in this system. In addition, the recombination junctions within the SV 40 portion of the integrants correlate with VM-26-induced, topoisomera se II cleavage hot spots on SV40 DNA. These results suggest a direct a nd specific role for topoisomerase II and possibly the enzyme-inhibito r-DNA ternary cleavable complex in integration. The propensity of pois oned topoisomerase II to induce viral integration also suggests a role for topoisomerase II in a pathway of chromosomal DNA rearrangements.