8 Non-programmed and Engineered Chromosome Breakage

Abstract

The integrity of the chromosome as a genetic package is central to the essential processes of meiosis and mitosis. Our ability to construct genetic and physical maps of genomes is based on this stability, a key component of which is provided by the telomere’s role in replicating the end of the DNA molecule contained in the chromosome and also protecting it from recombination. DNA introduced into the nucleus of a mammalian cell does not exist as an independent molecule but becomes integrated into the existing chromosomes. In contrast, the chromosomes themselves cannot normally undergo nonhomologous recombination because dicentric and multicentric chromosomes would result. Where two active centromeres are present on a single chromosome, forces imposed on the two centromeres may attempt to segregate them to different cells at cell division and result in chromosome breakage. If breakage in chromosomes that naturally have only a single centromere results in loss of the acentric fragment produced and the end of the centromeric part is not healed, the chromosome enters successive rounds of breakage-fusion-bridge cycles. These cycles can be terminated by healing of the break or, presumably, by cell death as a result of loss of genetic material. In yeast a single break in the genome can be sensed by the cell and results in arrested cell division. Equivalent checkpoint mechanisms probably also exist in mammalian and other cell types, with the p53 gene as an example. Loss of DNA or cell cycle perturbations are deleterious, and in mammalian systems, chromosome breaks are...