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The mysteries of DNA
August 29, 2012   
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Marcin Nowotny, Ph.D., head of the Protein Structure Laboratory at the International Institute of Molecular and Cell Biology in Warsaw, has been awarded an International Senior Research Fellowship Renewal grant from the Wellcome Trust, a London-based charitable foundation, for research into the mysteries of DNA.

The funds are intended for a research project entitled “Structural and Biochemical Studies of Holliday Junction Resolution,” which follows on from a Wellcome Trust International Research Fellowship that Nowotny started in 2008 and plans to complete this year. The renewal of the fellowship reflects an excellent track record during the first four years of the fellowship, with the successful establishment of an independent research lab and several excellent publications by Nowotny. His new project proposal has been rated as ambitious and interesting. The fellowship is for a period of five years between 2013 and 2017.

Previously, Nowotny won an ERC Starting Grant from the European Research Council and a prestigious International Early Career Award (IECS) from the U.S. Howard Hughes Medical Institute (HHMI).

Although the subject of Nowotny’s new research project is concerned with a field similar to that covered by the ERC grant, the two research projects do not overlap. Research conducted as part of these two projects is related to two different groups of proteins and different enzymes whose shared feature is that they are responsible for repairing genetic material.

“The code for every living organism is stored in the DNA,” says Nowotny. “All information on the body is encoded there. The DNA is a chemical compound that can undergo damage. Some kinds of damage are spontaneous, occurring over time, others are associated with external factors, such as solar ultraviolet radiation.”

The DNA in the cell is subject to random chemical modification, which may damage the genetic information. Therefore, damage repair processes are key to maintaining the stability of genetic material. In evolution, a number of efficient pathways have developed that play this role. Each body has a sophisticated system of mechanisms that repair such damage. The “recipe” for the body must remain intact.

Nowotny, aided by a group of colleagues, is examining some elements of these pathways that are unknown or little known to researchers.

The basic method used by molecular biologists is protein crystallography. All DNA repair pathways are protein-based. Crystallography makes it possible to determine with high precision how atoms are arranged in protein molecules, which allows researchers to precisely determine how the protein works.

The method involves the creation of protein microcrystals (less than a millimeter in size), which are then exposed to X-rays. Through various physical phenomena that occur and using special computer programs, the researchers can recreate the arrangement of atoms in protein molecules that make up the crystals.

“Our research methodology will allow us to gain an insight into the spatial structures of specific enzymes,” Nowotny says. “To clarify the role of these enzymes, it should be said that, during the repair of the DNA, unusual structures begin to appear in the cell as well as atypical forms of nucleic acid, where, for example, two helices are joined together. To make sure this does not lead to further problems, these helices must be separated and ordered. There is a special group of enzymes that deal with this. It’s precisely this group of enzymes that we want to study in the project for which the Wellcome Trust funds have been awarded.”

In each cell there are two copies of a gene. If one of these copies is damaged, the cell has special mechanisms that use the good copy to repair the bad one. In this process, however, fragments of the DNA must be joined together. After this process is completed, the enzyme which separates these two fragments springs into action.

“We want to examine the enzymes that deal with this separation process, because virtually nothing is known about how they work. We do not know how they recognize and find the joined pieces of the DNA, and then how they handle their separation; we also know very little about the chemistry of this process,” says Nowotny.

“Our research is not aimed at developing new treatments, but the more we learn about all these processes, the better chance we have of dealing with these problems in a practical way. The use of DNA repair pathways is not the only strategy to try to cure cancer but can be the basis for developing a new approach,” says Nowotny.

The procedure of qualifying the project for funding from the Wellcome Trust ended in May. The project will start in 2013 and run for five years.

Alongside the HHMI, the Wellcome Trust, founded by Henry Wellcome, is one of the world’s largest foundations financing scientific research. For several years, the Wellcome Trust has run a program of fellowships for researchers from developing countries. Poland is covered by this program and several researchers have received funds for their work.

“The Wellcome Trust International Research Fellowship which I received in 2007 allowed me to organize and equip a laboratory at the International Institute of Molecular and Cell Biology in Warsaw,” Nowotny said. “The fellowship comes with an extension option; the criteria are competitive and quite strict. I am delighted that we have managed to secure the fellowship renewal and that our research achievements have been highly rated.”

With the money offered by the Wellcome Trust, Nowotny will be able to hire two research assistants, buy equipment and cover travel expenses.

Karolina Olszewska
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