Chromosomal Instability and Its Relationship to Other End Points of Genomic Instability1

Chromosomal destabilization is one end point of the more general phenomenon of genomic instability. We previously established that chro mosomal instability can manifest in clones derived from single progenitor cells several generations after X-irradiation. To understand the potential 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 derived from the human-hamster hybrid line GM10115, which contains a single copy of human chromosome 4 in a background of 20-24 hamster chro mosomes. These clones were then subjected to a series of assays to determine whether chromosomal instability is associated with a general "imitator phenotype" and whether it modulates other end points of genomic instability. Thus, we analyzed clones for sister chromatid ex change, delayed reproductive cell death, delayed mutation, mismatch repair, and delayed gene amplification. Statistical analyses performed on each group of chromosomally stable and unstable clones indicated that, although individual clones within each group were significantly different from unirradiated clones for many of the end points, there was no significant correlation between chromosomal instability and sister chro matid exchange, delayed mutation, and mismatch repair. Delayed gene amplification was found to be marginally correlated to chromosomal instability (/' < 0.1), and delayed reproductive cell death (the persistent reduction in plating efficiency after irradiation) was found to be signifi cantly correlated (/' < 0.05). These correlations may be explained by chromosomal destabilization, which can mediate gene amplification and can result in cellular lethality. These data implicate multiple molecular and genetic pathways leading to different manifestations of genomic in stability in GMI0115 cells surviving exposure to DNA-damaging agents.