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A protein known for helping cells in repairing DNA damage, is also involved in the self-destruction of cells when the DNA damage is too large. This is the outcome of research of Scientists of the Mayo Clinic in Rochester, Minnesota, and has been published in the 13 October Science. [1]
Cell division is one of the most hardest and amazing processes in the human body. Thousands of genes, consisting out of over 3 billion base pairs, need to be copied without mistake. Mistakes happen, though. A erroneous copied gene may have severe consequences, especially during development. Because of this, the body has an extensive control and repair mechanism. This mechanism should ensure that errors are tracked down, and resolved if possible. In the worst-case scenario, the mechanism should lead to the 'self-destruction' of the cell, known as apoptosis.
One of the most important groups of enzymes in this process are the 'cyclin dependent kinases', or CDK's. One of them, CDK2, is active during normal cell division. When an error is found in the newly formed DNA chains, however, a complicated biochemical proces is started which leads to the inactivation of the CDK2 enzyme. As a consequence, the cell division halts, allowing for repair.
But when the damage is too extensive, the programmed cell death (apoptosis) mechanism starts. The researchers wondered if CDK2 could be involved in this process too. They investigated if there was a connection between CDK2 and a protein involved in the start-up of apoptosis, FOXO1.
The research showed there was a connection between the two indeed. When everything is normal, CDK2 transfers a phosphate group to the FOXO1 protein. Because of this phosphate group the FOXO1 isn't capable of activation of the apoptosis inducing genes. With extensive damage to the DNA, however, the CDK2 isn't active and doesn't transfer the phosphate group. This way the FOXO1 protein will start the fatal apoptosis mechanism, and the cell is killed.
More research is needed, though. The researchers weren't able to explain, however, how the inactivation of CDK2 leads to repair when there is little damage, and to cell-death whene there is extensive damage. Some sort of threshold could be involved.
Nonetheless this discovery may explain why some forms of cancer are resistant to chemotherapy and radiotherapy. These forms of therapy cause enormous damage to the DNA of targeted cells. But when deregulation of CDK2 would be involved, this would not only stop the repair of DNA, and thereby create a higher risk for cancer, but would also prevent the effectiveness of therapies.
[1] http://www.sciencemag.org/cgi/reprint/314/5797/294.pdf . Requires subscription.
