DNA polymerases in replication and repair of DNA during carcinogenesis induced by feeding N-acetylaminofluorene

To study the roles of DNA polymerases and ß duringreplication and repair of damaged DNA, use was made of the factthat during chronic treatment with carcinogens, replicationand repair do not necessarily follow the same time sequence.Early cell damage and restorative hyperplasia cause a transientwave of DNA synthesis, while repair replication might be expectedto continue throughout the period of treatment with the carcinogen.N-acetylaminoflluorene (AAF) was fed in the diet for periodsof up to 35 weeks, and at intervals during the feeding periodmeasurements were made of DNA synthesis in vivo, and off DNApolymerases a and ß as assayed in vitro after fractionation.The activity of polyararise increased and decreased with thetransient early wave of DNA synthesis. Polymerase ßshowed an initial rapid increase in activity which peaked beforethe increase in DNA synthesis, and then decreased. The decreasein activity may be due to the fact that, although AAF continuesto be fed in the diet, the foci and nodules which develop nolonger metabolise the carcinogen to a form which damages DNA.Thus replication occurs in the nodules while DNA damage andrepair occur in the surrounding non-neoplastic liver. With therapid growth of nodules there is overall an increase in neoplastictissue, a relative decrease in nonneoplastic tissue, and thusa relative decrease in DNA damage, repair, and induction ofpolymerase ß. Histo-logical examination showed thatby 35 weeks the conversion to neopflasia was virtually complete.These results support the concept that polymerase functionsin de novo replication of DNA, and is induced during cell replication,while polymerase it functions in repair replication, and increasesin activity during chronic damage to DNA. Whether it is inducedby treatment with carcinogens depends on the duration of treatment,and on other processes (e.g. metabolism of the carcinogen) whichtake place during the development of malignancy.