Anoxia-inducible Endonuclease Activity as a Potential Basis of the Genomic Instability of Cancer Cells1

Normal rat fibroblasts exhibit a staged response to anoxia which in several respects parallels processes activated in malignant tumor cells. We describe here a new element of the anoxic response, the induction by anoxia of a sequestered endonuclease activity. Such activity is elevated approximately 3-fold within anoxic fibroblasts and during Hirt DNA isolation is able to digest chromatin to produce a nucleosomal ladder. However, DNA is not measurably affected within intact cells, and cells retain complete viability as the endonuclease is induced. The anoxiainducible endonuclease acts without specificity for DNA sequence. Trace leakage of this endonuclease into the nucleus has obvious poten tial to underlie the known propensity of anoxic cells to undergo ampli fication and may be associated with the break-related genomic instabil ity of cancer cells.