Macromolecular machines and their mechanismes of action

DNA replication, recombination and repair are the most basic, strictly regulated processes coordinated by highly specialized nucleoprotein complexes, also known as “molecular machines” and made up of enzymes with different functions. Our group’s research interests centre on understanding the basic principles that underlie the formation of such multi-protein complexes, describing their structure, and determining their mechanism of action. Knowing how molecular machines copy and repair DNA will allow us to explain how errors in these key processes may lead to cell dysfunction and cause disease.

Michał Szymański with PhD student Marta Grzelewska. Photo by One HD/ FNP Mitochondria, often described as the “cell’s power plant”, generate the energy that each cell needs to survive and that our body requires for normal function. They have their own genetic material, known as mitochondrial DNA, which provides a set of precise instructions according to which the building blocks of the “power plant” are made. Any damage to mitochondrial DNA that results in mutation may contribute to mitochondrial dysfunction. Mitochondrial dysfunction, on the other hand, is linked to the processes of aging, as well as many medical conditions, including cancer, metabolic disease (e.g. diabetes), and various neurodegenerative disorders (e.g. Alzheimer’s disease). It turns out that mitochondria have their own set of repair tools, including specialized enzymes that identify and repair damaged mitochondrial DNA. Their mechanism of action, however, is still largely unknown.

The purpose of our project was to provide basic structure-function data to discover the mechanism by which damaged genetic material is identified by enzymes involved in mitochondrial DNA repair. We showed that the enzymes involved in identifying and eliminating DNA damage cooperate with one another, and that the process of identification and repair is stimulated by other proteins still. In addition, the POLONEZ grant allowed us to continue our international cooperation with a group run by Professor Andrew Fire from Stanford University, USA, which led to an article entitled “Transcription polymerase-catalyzed emergence of novel RNA replicons”, published in “Science”. In cooperation with teams from Poland and Slovakia, we described the first case of a homozygous variant of the POLG2 gene in an adult patient. Entitled “Whole exome sequencing identifies a homozygous POLG2 missense variant in an adult patient presenting with optic atrophy, movement disorders, premature ovarian failure and mitochondrial DNA depletion”, our joint article was published in the “European Journal of Medical Genetics”. In addition, the POLONEZ grant helped to generate the preliminary data and ideas for my ERC Starting Grant proposal.