The project aims to increase our understanding of the role of chromosome metabolism in cancer biology by studying the basic processes of recombination, replication, repair, and the relationship between structure and function. The cytotoxic drug alpha-sarcin inactivates ribosomes by cleaving a single bond in 28S RNA even though it hydrolyzes """"""""naked"""""""" RNA on the 3' side of all purines. The mammalian mitochondrial dihydroorotate dehydrogenase has been isolated and purified, and we have determined the stereochemical course of the reaction of this critical enzyme in pyrimidine biosynthesis. This information is useful in the design of stereoselective inactivating drugs. Studies of the special repeating DNA sequences in chromosomes have uncovered three types of poly CA tracts: at the tips, nearby, and at single copy sequences located internally on the chromosomes. A haploid meiosis system has been used to define the mode of action of different classes of recombination-control genes. Studies of replication and transposition have shown that the Pseudomonas virus D3112 and its cts mutant are """"""""mutator"""""""" phages similar to phage Mu of E. coli, which produces mutations by insertion. Treatment of lymphoid cells with high concentrations of alkylating agents results in diminution of the ATP supply in the cells due to the formation of poly (ADP-ribose), thereby inhibiting DNA repair. Blocking formation of the polymer restores repair capability. These interactions may account for the inhibitory effect of alkylating agents on UV-induced repair. Replication of the bacteriophage N4 requires two new N4 and two host proteins. The DNA has 3' single-stranded ends with a unique left end. A repeated sequence, 150 base pairs in length, is present in 1-20 copies and is located at or close to the region in which N4 DNA replication originates. (V)
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