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Escape from Senescence in Hybrid Cell Clones Involves Deletions of Two Regions Located on Human Chromosome 1q¹

Department of Pathology, University Hospital, Dag Hammarskjölds v. 20, S-751 85, Uppsala [C. K., Y. P., E. B-R., B. W.]; Department of Cell Biology, Faculty of Health Sciences, Linköping University, S-541 85, Linköping [G. S.]; Sweden; Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [P. J. V., J. C. B.]; and Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 [P. J. V., J. C. B.]

Human normal cells have been shown to undergo a limited number of cell doublings, a phenomenon termed cellular senescence. Human chromosome 1 has been implicated in this process, and several lines of evidence indicate that there is a senescence-inducing gene or genes on human chromosome 1q. Our approach to analyze the senescence-inducing effect of chromosome 1 includes the use of somatic cell hybrid revertants. We show here that fusion of a hypoxanthine phosphoribosyl transferasenegative mouse cell line (A9) containing a human neo-tagged chromosome 1 with an immortal hamster cell line (10W-2) results in cell hybrids that senesce after a few population doublings. Rare revertants that had escaped senescence were obtained after one large fusion experiment. Thirty-five nonsenescent hybrids were obtained from a total of approximately 1 million hybrids, and 25 of these were subjected to further analysis. The presence of a single copy of human chromosome 1 in the revertant hybrids was confirmed by fluorescence in situ hybridization analysis using a chromosome 1-specific painting probe. No visible translocations or deletions of chromosome 1 were observed in any of the hybrids. Deletion mapping revealed that 11 (56%) of the hybrids analyzed had lost one or more markers on chromosome 1q. Two regions with deletions were detected, one of which has been shown to be implicated in the senescence-inducing effect exerted by chromosome 1 following monochromosome transfer (P. J. Vojta et al., manuscript submitted for publication). The present study suggests that two separate loci on human chromosome 1q may be of importance for the induction of senescence. Moreover, this set of nonsenescent revertants could be useful for future detailed analyses of the senescence-inducing loci.

¹ This work was supported by the Swedish Cancer Society, Magn. Bergvalls Foundation, and Pharmacia AB.

² To whom requests for reprints should be addressed. Phone: 46-18-66 38 27; Fax: 46-18-55 89 31.

Received 10/ 5/95. Accepted 11/28/95.