DNA "Repair Enzymes" Tricked into Producing Mutations


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Prof. Zvi Livneh and Orna Cohen-Fix. Alternative mutation pathway

Vital "repair enzymes" responsible for preventing genetic mutations are at times hoodwinked into causing such mutations themselves, according to a recently published Institute study. It is known that environmental stress factors such as ultraviolet light or certain chemicals may create lesions on DNA strands, preventing the DNA molecule from issuing clear instructions on how to form an identical replica of itself. Were it not for the "rescue" operations of special "repair enzymes" -- proteins that search for lesions, cut them away and replace them with healthy DNA material -- mutations would be formed in uncontrollable fashion. However, Prof. Zvi Livneh and doctoral student Orna Cohen-Fix of the Department of Biochemistry have now found that these same enzymes can be duped into producing the very mutations they are designed to avert.

"Our hypothesis," says Prof. Livneh, "is that this occurs when two different lesions face one another on complementary DNA strands." The restoration procedure starts out normally, with the repair enzyme excising one of the lesions. "Then however," says Livneh, "the enzyme encounters an unexpected situation. The reserve store of information on the opposite strand, which it uses in order to fill in the gap, turns out to be faulty as well. A point of no return has been reached in the process, and the enzymatic machinery is left with no choice other than to proceed with the repair operation and to duplicate the defective material -- thereby producing a mutation."

This newly discovered process appears to be an "alternative" mutation pathway. In the more commonly recognized mechanisms, ordinarily dormant proteins called bypass factors help the DNA copying machinery to progress through lesions, thus generating permanent mutations in the cell's genetic material.

Livneh and Cohen-Fix used an original model system in which ultraviolet (UV) light-induced genetic changes are produced in test tubes by a protein extract from the bacterium Escherichia coli. The planned adaptation of this model to UV-exposed mammalian cells will allow the investigation of such dual pathways in mammalian systems, including those of humans.

Support for this work has been provided by the U.S.-Israel Binational Science Foundation and the Minerva Foundation, Munich, Germany.

Schematic diagram of lesion entering DNA duplicating machinery