CHROMOSOMAL INSTABILITY AND ITS RELATIONSHIP TO OTHER END-POINTS OF GENOMIC INSTABILITY

Chromosomal destabilization is one end point of the more general pheno menon of genomic instability. We previously established that chromosom al instability can manifest in clones derived from single progenitor c ells several generations after X-irradiation. To understand the potent ial relationship between chromosomal destabilization and the other end points of genomic instability, we generated a series of chromosomally stable and unstable clones by exposure to X-rays, All clones were der ived from the human-hamster hybrid line GM10115, which contains a sing le copy of human chromosome 4 in a background of 20-24 hamster chromos omes, These clones were then subjected to a series of assays to determ ine whether chromosomal instability is associated with a general ''mut ator phenotype'' and whether it modulates other end points of genomic instability, Thus, we analyzed clones for sister chromatid exchange, d elayed reproductive cell death, delayed mutation, mismatch repair, and delayed gene amplification, Statistical analyses performed on each gr oup of chromosomally stable and unstable clones indicated that, althou gh individual clones within each group were significantly different fr om unirradiated clones for many of the end points, there was no signif icant correlation between chromosomal instability and sister chromatid exchange, delayed mutation, and mismatch repair, Delayed gene amplifi cation was found to be marginally correlated to chromosomal instabilit y (P < 0.1), and delayed reproductive cell death (the persistent reduc tion in plating efficiency after irradiation) was found to be signific antly correlated (P < 0.05). These correlations may be explained by ch romosomal destabilization, which can mediate gene amplification and ca n result in cellular lethality. These data implicate multiple molecula r and genetic pathways leading to different manifestations of genomic instability in GM10115 cells surviving exposure to DNA-damaging agents .