Involvement of DNA damage in hydroxyurea-mediated induction of endogenous murine retrovirus

Abstract

Hydroxyurea (HU) induces AKR cells to produce endogenous murine retrovirus at a low frequency (approx. 1 x 10/sup -5/), and DNA synthesis is required soon after treatment with HU for induction to be observed (i.e., no stable induction intermediate is formed). Induction by HU can be enhanced by simultaneous treatment with halogenated pyrimidines, with the concomitant appearance of a stable induction intermediate state. The effects of the two compounds are synergistic, indicating an actual stimulation of HU-mediated induction by iodode-oxyuridine. Since HU inhibits semiconservative replication, and since (/sup 3/H)bromodeoxyuridine is incorporated into the cellular genome predominantly by unscheduled DNA synthesis (repair replication) under these conditions, this stimulation appears to be the result of insertion into DNA of the thymidine analogs during the repair of HU-induced alterations in the DNA. The nature of HU damage to DNA is not defined; if single-strand breaks are involved, they may occur at a frequency <10/sup -8/ and escape detection, but induction could also be due to other alterations in DNA. The characteristics of induction by HU, therefore, are similar to those of induction by other DNA-damaging treatments such as ..gamma.. or x irradiation or methylcholanthrene. This suggests that these agents may induce by similar,more » if not identical, mechanisms. Further, the ability of halogenated pyrimidines to form a stable induction intermediate when incorporated by repair synthesis, similar to the intermediate formed when the analogs are incorporated during semiconservative replication, suggests that the same sites are involved for induction by damaging agents or by halogenated pyrimidine incorporation.« less