Download ERC funds Polish research into genetic material repair pathways

Ministerstwo Nauki i Szkolnictwa Wyższego
ERC funds Polish research into genetic material repair
pathways
DNA repair mechanisms are key processes not only for cognitive reasons, but also because in
humans DNA disorders may lead to the formation of tumours.
Dr. Marcin Nowotny, head of the Protein Structure Laboratory of the International Institute of Molecular and Cell
Biology in Warsaw, studies genetic material repair pathways in a project funded by a grant from the European
Research Council (ERC Starting Grant). "The recipe for every living organism is stored in DNA. All information on
the body is encoded there. DNA is a chemical compound that can suffer damages. Some damages are
spontaneous, occurring over time, others are associated with external factors, such as solar ultraviolet
radiation" - said Dr. Nowotny. DNA in the cell is subject to random chemical modification, which may damage
the genetic information. Therefore, damage repair processes are the key to maintain the stability of genetic
material. In evolution, a number of very efficient pathways have developed that fulfil this role. Each body has a
sophisticated system of mechanisms that repair such damage. "Recipe" for the body must remain intact.
Structural studies of selected elements of these pathways are the subject of a project funded by the ERC.
Working Together with Dr. Nowotny on the European project are Marcin Jaciuk, Michał Burbot and Marzena
Nowacka, involved in the experiments. The basic method used by molecular biologists is protein
crystallography. All DNA repair pathways are protein based. Crystallography allows to determine with high
precision how atoms are arranged in protein molecules, and thus allows to precisely determine how the protein
works. The method involves the creation of protein microcrystals (size below a millimetre), which then are
exposed to X-rays. Through various physical phenomena that occur and the appropriate computer programs,
researchers can recreate the arrangement of atoms in protein molecules that make up crystals. Research of Dr.
Nowotny is regarded as fundamental, it is therefore difficult to speak of its practical application. The project is
not intended to have any application, but learning about DNA repair pathways is very important. When genetic
material of a cells is disturbed, there are mutations, changes in genetic code. They lead to disturbance of
different processes in cells and their uncontrolled growth, and thus to the formation of tumours. "Cancer cells
are very often unable to repair the DNA. Many anticancer drugs damage DNA, and when the cancer cell can not
handle it, it dies. Exploring these processes is very important for the subsequent work on new drugs or
therapies" - said Dr. Nowotny. The project at the Institute of Molecular and Cell Biology consists of three parts.
The first part concerns the bacterial DNA repair pathway, NER (Nucleotide Excision Repair). The pathway
involves two proteins. One of them locates DNA damage, and the second verifies its presence. Researchers
have found that damage detection does not occur by direct interaction with the modification place, but by
detecting the DNA deformation caused by damage. In the ERC project they want to learn the next steps in the
mechanism of bacterial NER pathway, solve complex crystal structure of both DNA proteins and determine, how
the DNA is transferred to another protein and how it verifies the presence of damage. The second part of the
project concerns the eukaryotic NER pathway, in which proteins function that are unrelated to proteins from the
bacterial path. One such protein is XPG benzonase, involved in final stages of NER. Its role involves cutting the
DNA fragment containing the damage. There are no structural data on the protein, and details of its mechanism
of action remain unknown. Therefore, Dr. Nowotny’s team is working on determining its spatial structure in the
complex with the nucleic acid, in order to explore this mechanism. The third part of the project concerns the
DNA repair complex Rad16-Rad7 present in yeast, whose role is to repair damage untranscribed strands of
active genes. Researchers are intrigued with the fact that this complex has two activities. The first is the
helicase activity, which allows the complex to move along the DNA to detect damage, and the second is
ubiquitin ligase activity, whose role is probably to communicate Rad16-Rad7 with other DNA repair pathways.
Mechanisms of action and coordination of both activities are unknown. Therefore, scientists will apply a
combination of structural and biochemical methods to determine these mechanisms. PAP - Science and
Scholarship in Poland, Karolina Olszewska
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