Projects Offered

1 PhD project offered in the IPP summer call Molecular Mechanisms in Genome Stability & Gene Regulation

Scientific Background

The Hofmann group at the Institute of Toxicology at the University Medical Center in Mainz (https://www.unimedizin-mainz.de/toxikologie/overview.html?L=1) investigates the role of DNA damage and DNA repair in cell fate regulation with focus on cancer. The PhD project offered is embedded in the DFG-funded 4R graduate program (GRK) (https://4r-rtg.de), which is dedicated to better understand the function, regulation and biology of RNA:DNA hybrids termed R-loops. R-loops are three-stranded RNA-DNA hybrids of an RNA that invades an DNA duplex and are largely formed in a co-transcriptional manner. Although R-loops fulfill beneficial regulatory functions in gene expression and telomere stability, unscheduled R-loop formation and persistence of R-loops can drive replicative stress, DNA damage and genomic instability, which is a hallmark of cancer. Loss of specific tumor suppressor genes is frequently observed in human cancer, and has been linked to increased replication stress and genome instability. Our unpublished results indicate an unforeseen link between loss of specific tumor suppressors, increased R-loop formation and genome instability. Since unscheduled, persistent R-loops can trigger the DNA damage response through activation of DNA damage checkpoint kinases, increased R-loop formation in cancer cells may provide novel therapeutic strategies for treatment of such cancer entities. This project will address the molecular link between loss of specific tumor suppressors, R-loop formation and the resulting biological responses in cancer cells. A particular focus of this project is to exploit the identified molecular links as potential Achilles heel to target cancer cells with loss of specific tumor suppressor genes. 

The project will be performed in close interaction with the Genomics and proteomics core facilities at IMB Mainz, and in collaboration with several groups of the 4R GRK consortium in Mainz.

PhD Project: R-loops in cancer cells: an Achilles heel to target cancer cells?

Our unpublished data indicate that loss of a specific tumor suppressor (TS) gene results in an increased, unscheduled R-loop formation. This increased R-loop formation is linked to replication stress and activation of the DNA damage signaling network. Aim of this PhD project is to study the underlying mechanism of R-loops formation and its role in genome instability and cancer cell sensitivity to therapy by addressing the following scientific questions will be addressed by applying multiple methods and techniques from molecular biology, cell biology and biochemistry: 

(1.) How does the loss of the tumor suppressor trigger increased R-loop formation and genomic instability, (2.) where in the genome do these R-loops arise (using genome-wide R-loop mapping using sequencing technologies)? (3.) Which DNA damage checkpoint kinases are activated by the persistent R-loops, and by which mechanism? Is there an increase in cytoplasmic R-loops (using R-loop sensor and confocal microscopy) and thereby activation of the innate immune response and pro-inflammatory signaling? (4.) Which negative regulators of R-loops (helicases, nucleases and RNA-binding proteins) are involved in balancing increased R-loop formation in cancer cells with loss of specific tumor suppressor? (5.) Identification of the R-loop-associated proteome in cancer cells with loss of specific tumor suppressors (using IP-mass spectrometry) (6.) Can we exploit the increased R-loop formation to increase sensitivity of cancer cells to therapy? 

If you are interested in this project, please select Hofmann as your group preference in the IPP application platform.

Publications relevant to this project

Wells JP, White J, Stirling PC (2019). R-Loops and their composite cancer connections. Trend in Cancer 5. Link

Niehrs C and B Luke (2020). Regulatory R-loops as facilitators of gene expression and genome stability. Nat Rev Mol Cell Biol 21:167-178. Link