Germ cell DNA-repair systems-possible tools in cancer research?
A major dogma in cancer research is that cancer begins at the cellular level. Because of this single-cell origin, evolutionary principles have often been used to explain how somatic cancer cells are selected at a sub-individual level. The traditional application of Darwinian theory, however, in which the colony of cells constituting an individual is regarded as a whole, has not been applied extensively to the understanding of cancer until recently. Two proponents for this view, Breivik and Gaudernack, have suggested that in certain situations the cost of DNA repair might exceed the cost of errors. This model predicts that genetic stability is configured for an optimal cost-benefit relationship. Natural selection is not expected to have produced the best genetic stability available in the human body, merely the best compromise of DNA repair and costs. Repair and maintenance of the vast human genome is thermodynamically expensive, and an optimal balance between DNA repair and dietary needs is likely to have originated. Furthermore, fast growth conveys significant advantages such as early maturation or cognitive development, but usually at the expense of replication accuracy. Thus, a compromise between growth speed and cancer risk is likely to have taken place. These and other ecological mechanisms have probably prevented genomic stability to reach its full potential in the human body. In contrast, germ lines express near perfect DNA maintenance. Although germ cells are specialized DNA-conserving cells with few other functions, it's not given that their proteins will all be incompatible with the somatic cell. One approach to study this would be to systematically explore which DNA-stability and -repair systems are unique in germ cells, and induce their expression in invertebrate and mammalian model organisms. This could unveil which DNA-repair systems are switched off in the somatic cell lines, as they are incompatible, and which are absent due to evolution. The present review discuss different DNA-repair systems and cell cycle check point control mechanisms shown to be different or unique in the germ cell, and how they may be utilized in cancer therapy.
Renal Research Group, Institute of Medicine, University of Bergen, Bergen, Norway. Frank.Helle@med.uib.no
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D000818:Animals; D004260:DNA Repair / Q000502:physiology*; D005786:Gene Expression Regulation; D042822:Genomic Instability; D005854:Germ Cells / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D012106:Research / Q000639:trends