DNA instability, telomere dynamics, and cell transformation

Abstract

In differentiating eukaryotes, recombination occurs both in mitosis and in meiosis, where it may involve overlapping but distinct genetic pathways. Meiotic recombination—in germ-line cells only—augments the reassortment of gene alleles accomplished by the segregation of chromosomes at the first meiotic division. Because mitoses greatly exceed meioses in lineages leading to gamete formation, mitotic recombination also contributes greatly to germ-line reassortment and rearrangement of genes. Moreover, meiotic recombination between homologous DNA sequences of multigene families plays a significant role in generating genetic diversity and facilitating the evolution of genes. Mitotic recombination plays a crucial role in repairing DNA damaged by a variety of agents, both in somatic tissues and in gametic lineages. Additionally, mitotic homologous recombination in somatic cells mediates immunoglobulin class switching and may underlie the loss of heterozygosity that, in regions containing anti-oncogenes, contributes to carcinogenesis. Recombination can be elevated by a variety of agents—chemical carcinogens, radiation, and oncogenic viruses—which might elicit an increased abundance of substrates and/or of enzymes mediating recombination. Telomeres—specialized nucleoprotein structures at the ends of chromosomes—contribute to genomic integrity by protecting genomic DNA from degradation and end-to-end joining of chromosomes. The transgenic expression of the human telomerase reverse transcriptase (hTERT) within normal human fibroblasts and retinal epithelial cells in culture greatly extends their replicative life spans without inducing the changes characteristic of malignant cells. These observations establish the important point that a deficiency of telomerase alone and more precisely of the telomerase catalytic subunit, limits replicative potential in cultured human cells.