Bergler group - 60S biogenesis

A. The function of the AAA-ATPase Drg1 in 60S ribosomal subunit maturation

The biogenesis pathway of the large ribosomal subunit starts in the nucleolus with the formation of precursor (pre-60S) particles and is finalized in the cytoplasm where the last maturation steps take place. These final steps include the release of shuttling proteins and export factors from the pre-ribosomal particle as well as the incorporation of the last ribosomal proteins. A key player in this process is the AAA-ATPase Drg1, which initiates cytoplasmic pre-60S maturation by releasing the shuttling protein Rlp24. Drg1 is composed of an N-terminal domain and two AAA-domains. Its ATPase activity is essential for the progression of pre-60S particles to more mature forms. The main focus of our research lies on the function of Drg1 and its mode of action at the molecular level. In particular, we want to understand how Drg1 interacts with its substrate protein and how the energy generated by ATP hydrolysis is then used to perform its essential function in ribosome biogenesis.

B. Identification and characterization of inhibitors of ribosome biogenesis

The formation of the large ribosomal subunit in eukaryotic cells requires more than 200 trans-acting factors, most of which are essential for survival. Since rapidly proliferating cells, particularly cancer cells, exhibit a high rate of ribosome synthesis, this process represents a promising target for anti-infective and anti-cancer chemotherapy. Indeed, we previously showed that a certain class of inhibitors specifically interferes with the formation of 60S ribosomal subunits. In this respect, we are highly interested in identifying possible targets and inhibitors that specifically interfere with ribosome biogenesis of eukaryotic cells.