Scientists Discover Enzymes Capable of Duplicating Damaged Genetic Material, Creating New Mutations

Genetic material (DNA) is damaged on a daily basis due to environmental factors, such as solar radiation and exposure to certain hazardous materials, as well as natural cell processes. This damage can leave chaos in its wake, scrambling or deleting the genetic 'letters' encoding an organism's traits. If left unchecked, the mutated DNA will continue to replicate, and may cause impaired protein production and disease.

Fortunately, all organisms employ various cellular DNA repair systems. In most cases, however, they perform on an 'all or nothing' basis: when unable to precisely correct the damage they stop operating, halting genetic replication entirely. The end result, even more severe than the initial damage, is that of cell death.

The key to life is therefore the cell's ability to 'compromise,' allowing DNA repair systems to operate with a certain 'sloppiness' that permits a small number of mutations. While this may pose a certain risk, it also ensures the cell's continued existence. Equally important, it increases genetic diversity allowing natural selection, the driving force behind evolution, to come into play.

Prof. Zvi Livneh of the Weizmann Institute's Biological Chemistry Department has discovered a group of enzymes that perform one such mechanism. His latest findings are reported in the Proceedings of the National Academy of Sciences (PNAS, USA).

Genetic material is constantly duplicated as an integral part of cell division and reproduction occurring in all living beings. In dividing, the cell unzips the DNA double helix (consisting of two winding strands linked together by matching base pairs) using each strand as a template to direct the formation of its companion strand. Overseeing this process is a unique enzyme known as DNA polymerase, that 'rides' on board the existing strand much like a train on a single track, reading its genetic sequence to form a matching strand. The result, generally achieved with remarkable precision, is two identical DNA molecules, each consisting of an original and a newly synthesized strand. Upon encountering damaged DNA, this duplicating enzyme usually stops in its tracks - which is where the specialized 'damage control' crews enter the scene.

Prof. Livneh has recently discovered one of these DNA repair mechanisms, based on a previously unknown group of polymerase enzymes. While these enzymes also duplicate genetic material, they usually do not stop when encountering damaged DNA. Instead, they duplicate the material, often creating new mutations.

According to Livneh, this family of enzymes, which is found in both humans and bacteria, is one of the most important factors preventing unnecessary cell destruction and driving the evolutionary process. The flip side, however, is that by enabling bacteria to rapidly evolve new genetic characteristics, these enzymes are also responsible for the increasing bacterial resistance to antibiotic drugs. The recent Weizmann Institute discovery of a particular member of this enzyme family, known as DNA polymerase R1, may open a new course of action against this growing health threat. By suppressing the activity of R1 and other similar DNA polymerases it may be possible to slow the spread of antibiotic-resistant bacteria.

Another potential application is the reconstruction of damaged DNA left at crime scenes, or ancient DNA found in the remains of prehistoric plants and animals. These two forms of DNA are often damaged (for instance, by cleaning detergents aimed at destroying the evidence left at a crime scene, or simply the ravages of time in the case of ancient DNA). 'Previous reconstruction attempts using known DNA polymerase agents were often hindered, since even localized DNA lesions can cause these enzymes to stop operating, dooming the entire reconstruction process,' explains Livneh. 'The 'sloppy' R1 duplicating enzyme may prove pivotal in this respect due to its ability to tolerate damaged genetic material.'

Prof. Zvi Livneh holds the Maxwell Ellis Professorial Chair in Biomedical Research. His research is supported by the Dolfi and Lola Ebner Center for Biomedical Research and the Minerva Foundation, Germany.

The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel. Its 2,500 scientists, students and support staff are engaged in more than 1,000 research projects across the spectrum of contemporary science.