Vacant Positions

Fully funded PhD candidate position

 

The research laboratories of the Clinic of Gynecology seek a highly motivated postgraduate student for PhD studies in molecular cell biology regarding the role of PolyADP ribosylation in ribosome biogenesis and tumor cell growth.

Many breast and ovarian cancers are associated with defective homologous recombination (HR) pathways that are important for both DNA double-strand break repair and faithful DNA replication. Defective HR renders tumor cells hypersensitive to Poly ADP-ribose polymerase (PARP) inhibitors, a family of targeted drugs that have recently been admitted to the clinic and are currently used for the treatment of breast and ovarian cancer patients with defective HR.  

Intriguingly, recent evidence suggests that PARP inhibitors are sometimes also effective in patients with HR proficient tumors. The molecular mechanisms that lead to PARP inhibitor sensitivity in these cases are poorly understood, but PARP-dependent ribosome biogenesis was recently suggested to play a major role (1).

Ribosome biogenesis occurs in in the nucleoli, membrane-less organelles in the cell nucleus that contain the rDNA repeat clusters, which code for the majority of the ribosomal RNAs. Efficient ribosome biogenesis is also dependent on the adaptor proteins TCOF1/Treacle and the RNA helicase DDX21 (2). We have extensively characterized the role of TCOF1/Treacle in the cellular response to DNA breaks induced in the rDNA repeats (3-4). Interestingly, TCOF1/Treacle is also a substrate for ADP ribosylation by PARP enzymes, but the physiological role of this modification has not yet been addressed. 

The main goal of this project is to determine the molecular mechanisms by which PARP regulates ribosome biogenesis and to further investigate the potential of PARP inhibitors to shut down ribosome biogenesis in the nucleoli and thus reduce tumor cell growth and promote apoptosis.

Experimental methods include, besides state-of-the-art biochemistry and molecular biology methods, quantitative cell biology and single-molecule analysis. The successful candidate should hold a Master-degree in Biology or Biomedicine.

  1. Kim et al (2019). Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21. Molecular Cell, 75(6), 1270–1285.
  2. Calo et al. (2018). Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders. Nature, 554(7690), 1–30.
  3. Larsen et al. (2014). The NBS1-Treacle complex controls ribosomal RNA transcription in response to DNA damage. Nature Cell Biology, 16(8), 792–803.
  4. Mooser et al. (2019). Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recuitment and ATR activaiton. Nature Communications, in press

 

Master Thesis Projects

We also welcome intelligent and self-motivated students to perform a semester or degree project in our group. Please send us unsolicited applications via e-mail or visit the lab to inquire eventual positions.