The Kassube group studies the molecular mechanisms of Fe-S protein biogenesis and DNA repair.
We use an integrative approach employing biochemical and biophysical methods, deep learning-based protein structure prediction, and structural analyses by X-ray crystallography and cryo-electron microscopy, to shed light on the mechanisms of action of large macromolecular machines.
Fe-S protein assembly and DNA repair
Iron-sulfur (Fe-S) clusters are ancient inorganic protein cofactors of vast functional diversity. Found across all three domains of life, Fe-S clusters play key roles essential for life ranging from electron transfer, chemical catalysis, sensing of cellular oxygen and iron levels, to stabilizing protein folds. In eukaryotic cells, Fe-S clusters are not only found in mitochondrial respiratory chain complexes, but they are also essential cofactors for the cytosolic and nuclear proteome. In particular, Fe-S clusters are essential components of many proteins involved in DNA replication and DNA repair. While Fe-S clusters are essential for the functions of these DNA metabolism proteins, and pathological mutations in the Fe-S domains of XPD, FANCJ, RTEL1 and DDX11 are the underlying causes of trichothiodystrophy, Fanconi anemia, dyskeratosis congenita, and Warsaw breakage syndrome, respectively, the precise roles of their Fe-S clusters remain enigmatic. Given the cellular toxicity of free iron, the biogenesis of Fe-S proteins requires a tightly regulated, multi-step process, which has been highly conserved throughout evolution and relies on dedicated machineries in the specific cellular compartments.
Our research aims to obtain a detailed mechanistic understanding of the cellular pathways required for eukaryotic Fe-S protein assembly, and the functions and molecular mechanisms of Fe-S proteins involved in DNA repair.
RecQ helicases
RecQ DNA helicases play a critical role in genome maintenance and are often referred to as “guardians of the genome”. Mutations in three of the five human RecQ helicases have been linked to human genetic disorders, including Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome. These diseases are characterized by genomic instability, premature aging, and an increased risk of cancer. The RecQ helicase WRN has recently emerged as an attractive drug target due to its synthetic lethal relationship with microsatellite instability.
Our research aims to uncover the molecular mechanisms and regulation of RecQ helicases in different DNA repair pathways.