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

Departments of Molecular and Cellular Biology [D. L. S., G. R. A., C. A. R.] and Experimental Therapeutics [T. A. B.], Roswell Park Cancer Institute, Buffalo, New York 14263

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 anoxia-inducible endonuclease acts without specificity for DNA sequence. Trace leakage of this endonuclease into the nucleus has obvious potential to underlie the known propensity of anoxic cells to undergo amplification and may be associated with the break-related genomic instability of cancer cells.

¹ This work was supported by NIH research Grant CA48828 and United States Army Grant DAMD1791C1003 to G. R. A. and a grant to A. M. S. from the Italian Association for Cancer Research (AIRC), Milan, Italy.

² To whom requests for reprints should be addressed.

³ Visiting scientist from the Department of Biochemistry and Biophysics, University of Naples Medical School, Naples, Italy.

Received 10/14/91. Accepted 6/ 9/92.

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