16. Double strand break repair functions and gene amplification
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Abstract: It is known that DNA-PKcs is a key protein for the repair of DSBs through the NHEJ pathway and that DSBs can initiate gene amplification. The results obtained by Elena Giulotto and Chiara Mondello indicate that in human cells an impairment in DNA-PKcs function increases the proneness to DNA amplificaton. Promiscuous recombination events between broken ends, which are not immediately and correctly rejoined could trigger the amplification process. Alternatively, a defect in DNA-PKcs could cause an increase in gene amplification by altering the equilibrium between NHEJ and HR.
They also obtained human cell lines with good inhibition of DNA-ligase IV expression, however, the degree of protein level reduction was not related to sensitivity to IR, which was only slightly increased in some cell lines. This observation suggests that either low levels of the protein are sufficient for DSB rejoining or that other ligases, such as ligase III, can contribute to the repair of this kind of damage. On the other hand, the greatly reduced amplification ability of some ligase IV defective cell lines suggests that this protein may be essential for the recombination events accompanying gene amplification. To test this hypothesis they will analyze amplification in cell lines derived from mice in which the gene had been inactivated by homologous recombination.
The identification of genes playing a role both in radiation response and in gene amplification is relevant for the elucidation of the individual response to radiotheray. In fact, the rare cells surviving radiotherapy in tumours bearing mutations in genes which increase amplification frequency could be more prone to amplify oncogenes and drug resistance genes, giving rise to highly aggressive recurrences, in spite of their hyper-sensitivity to IR.