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Characterization of Chromosome Aberrations Induced by Incubation at a Restrictive Temperature in the Mouse Temperature-sensitive Mutant tsFT20 Strain Containing Heat-labile DNA Polymerase ¹

Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan

tsFT20 cells derived from a mouse mammary carcinoma cell line, FM3A, which has temperature-sensitive DNA polymerase activity (Y. Murakami, H. Yasuda, H. Miyazawa, F. Hanaoka, and M. Yamada, Proc. Natl. Acad. Sci. USA, 82: 1761–1765, 1985) were rapidly committed to death after temperature upshift to 39°C. tsFT20 cells synchronized in S phase were more sensitive to the restrictive temperature than exponentially growing cells. In order to gain insight into the processes from the interruption of DNA synthesis to cell death, we analyzed chromosome aberrations induced in tsFT20 cells which had been incubated for 2 or 4 h at the restrictive temperature and then cultured at the permissive temperature. The majority of metaphase cells showed extensive chromosome aberrations such as chromatid gaps, breaks, and exchanges; chromosome pulverizations; their mixed types; and ring chromosomes. Analyses with the use of cell synchronization and autoradiography revealed that chromosome aberrations were induced only in the cells which synthesized DNA during incubation at 39°C. We classified the chromosome aberrations into five types: gap or break type; exchange type; pulverization type; complex type; and ring type. The temporal order of the appearance of these types of chromosome aberrations was found to be the above described order. It was further found that cycloheximide dramatically repressed the induction of chromosome aberrations, and metaphases with many chromosome aberrations exhibited a large number of sister chromatid exchanges. These results indicate that abnormal cessation of DNA replication in tsFT20 cells at the restrictive temperature due to the inactivation of DNA polymerase results in cell death via induction of double-strand breaks which lead to chromosome aberrations as well as sister chromatid exchanges.

¹ This work was supported in part by Grants-in-Aid for Scientific Research and for Cancer Research from the Ministry of Education, Science and Culture, Japan, and by the Naito Foundation.

² To whom requests for reprints should be addressed.

³ Present address: Riken Gene Bank, The Institute of Physical and Chemical Research.

⁴ Present address: Hatano Research Institute, Food and Drug Safety Center.

Received 3/ 3/87. Revised 6/19/87. Accepted 6/24/87.

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