Genomic instability

The helicases are enzymes central to life itself. The nature of double-stranded DNA means that before a polymerase can begin to copy the appropriate region of the nucleic acid, the two strands have to be unwound the separation of the two strands is the function of the helicase (Fig. 2). An indication of the significance of this family of enzymes is seen in the so-called Werner syndrome, where the helicase function required in the suppression of inappropriate recombination events is defective and causes genomic instability and cancer (for a review see Cobb and Bjergbaek 2006). 

Coursen, J. D., W. P. Bennett, L. Gollahon, J. W. Shay, and C. C. Harris. 1997. Genomic instability and telomerase activity in human bronchial epithelial cells during immortalization by human papillomavirus-16 E6 and E7 genes. Exp Cell Res 235( 1 ) 245-53. 

Chromosomal instability and its relationship to other end points of genomic instability. Cancer Res. 57 5557-5563. 

Tumor cells differ from normal cells in one dramatic way they have lost the susceptibility to normal controls on cell proliferation. It should not surprise us then to learn that tumor suppressor genes and proto-oncogenes fall into one of three key categories. First, some oncogenic mutations directly affect cell proliferation. Second, other oncogenic mutations lead to loss of cell cycle control. Third, still other oncogenic mutations lead to genomic instability. 

Skorski T. BCR/ABL regulates response to DNA damage the role in resistance to genotoxic treatment and in genomic instability. Oncogene 2002 21 8591 8604. 

A single optimal CPD introduced into Sicl (called Sicl ) restores recognition and ubiquitination by SCF in vitro and degradation in vivo. However, in individual G1 phase cells, Sicl is eliminated well before cells pass Start, resulting in premature DNA replication, genome instability and lethality in a cdhl deletion background. 

Using the Columbia microbeam, Zhou et al. [4] passed one alpha particle through the nuclei of mammalian cells. When 10% of the cells were irradiated with a single alpha particle, the mutation yield was similar to that observed when 100% of the cells were irradiated. Clearly, a single alpha particle can induce genomic instability in cells that were not irradiated. 

Radiation-induced genomic instability and bystander effects are now well-established consequences of exposure of living cells to ionizing radiation. Cells not directly traversed by radiation may still exhibit radiation effects. This phenomenon, known as bystander effect, has become a major activity in radiation biology and in some cases has challenged the conventional wisdom. An example is the currently accepted models used for low-dose extrapolation of radiation risks. The currently used models assume that cells in an irradiated population respond individually rather than collectively. If bystander effects have implications for health risks estimates from exposure to ionizing radiation, then the question of whether this is a general phenomenon or solely a characteristic of a particular type of cell and the radiation under test becomes an important issue. 

The bystander effect has been observed for a variety of biological end points such as cell survival [158 159], mutation [160-162], sister chromatid exchanges [163], cell transformation [164,165], micronucleated and apoptosis [166], gene expression [167], and radiation genomic instability [168-170]. 

Sieber OM, Heinimann K, Tomlinson IP. Genomic instability the engine of tumorigenesis Nat Rev... 

Hernando E, Nahle Z, Juan G et al. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 2004 430 797-802. 

Chin K, de Solorzano CO, Knowles D et al. In situ analyses of genome instability in breast cancer. 

Grevelding, C.G. (1999) Genomic instability in Schistosoma mansoni. Molecular and Biochemical Parasitology 1 01,207-216. 

Fenech, M., Baghurst, P., Luderer, W., Turner, J., Record, S., Ceppi, M., and Bonassi, S. (2005). Low intake of calcium, folate, nicotinic acid, vitamin E, retinol, beta-carotene and high intake of pantothenic acid, biotin and riboflavin are significantly associated with increased genome instability—Results from a dietary intake and micronucleus index survey in South Australia. Carcinogenesis 26, 991-999. 

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