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

Scientific Background

The PhD project is embedded in the 4R GRK dedicated to a better understanding of R-loop biology. R-loops are three-stranded RNA-DNA hybrids of an RNA that invades an DNA duplex and mainly formed in a co-transcriptional manner. Although R-loops fulfill beneficial regulatory functions in gene expression and telomere stability, unscheduled R-loop formation and/or persistence can drive replicative stress and genome instability by causing transcription-replication conflicts. Loss of tumor suppressors and activation of oncogenes is a hallmark of cancer and has been linked to increased transcription-replication conflicts and R-loop formation. Unscheduled R-loops activate the DNA damage signaling cascade and therefore establish specific sensitivity to DNA damage checkpoint kinase inhibition. Interestingly, potential links between numerous tumor suppressors and R-loops have not been addressed so far and thus remain unknown. In addition, also the potential to exploit such links as potential Achilles heel to specifically target cancer cells remains unclear.    

PhD Project: R-loop regulation by tumor suppressors: 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Our unpublished data indicate that loss of a specific tumor suppressor (TS) gene results in an increased, unscheduled R-loop formation. The 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 or applying the following methodology and techniques: 

(1.) How does the loss of the tumor suppressor trigger increased R-loop formation and (2.) where in the genome do the R-loops arise (S9.6 Cut & Tag Seq)? (3.) Do we also find an increase in cytoplasmic R-loops and activation of innate immunity and the inflammatory response? (4.) Which negative regulators of R-loops (helicases, nucleases and RNA-binding proteins) are involved in balancing increased R-loop formation in cancer cells that lost this TS? (5.) Can we exploit the increased R-loop formation to increase sensitivity of cancer cells to therapy? The project will be performed in close collaboration with the Genomics core facilities at IMB and with colleagues of the 4R GRK.

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