Effects of metal treatment on DNA repair in polyamine-depleted HeLa cells with special reference to nickel.

Human cells depleted of the naturally occurring polyamines putrescine, spermidine, and spermine exhibit altered chromatin structure and marked deficiencies in DNA replicative and repair processes. Similar effects have been observed following treatment of normal mammalian cells with various heavy metal salts. In an attempt to better understand how metals interfere with normal DNA metabolic processes, a series of studies was carried out in which the toxicity and repair-inhibitory properties of various metals were evaluated in polyamine-depleted HeLa cells. Cytotoxicity of copper, zinc, magnesium, and cadmium was not altered in cells carrying lower polyamine pools. However, the sensitivity to nickel was markedly increased upon polyamine depletion, a condition that was readily reversed by polyamine supplementation. Nucleoid sedimentation analysis indicated that a greater amount of nickel-induced DNA damage occurred in polyamine-depleted cells than in normal cells, possibly serving as the basis for the increased sensitivity. Both polyamine depletion and nickel treatment result in decreased repair of DNA strand breaks and decreased cloning efficiency following X-ray and ultraviolet irradiation. Nickel treatment of polyamine-depleted cells resulted in synergistic sensitivity to both radiation treatments. None of the other metals tested enhanced X-ray or ultraviolet sensitivity of polyamine-depleted cells. Analysis of retarded repair sites following ultraviolet irradiation indicated those sites to be nonligatable in polyamine-depleted and nickel-treated cells, suggesting a block in the normal gap-sealing process.