PhD position: R-loops in genome stability, cancer & cancer therapy (m/f/d)Full PhD

Thinking of doing your PhD in the Life Sciences? The  International PhD Programme (IPP)  Mainz is offering talented, young scientists the chance to work on cutting edge research projects within the open call on “Molecular Mechanisms in Genome Stability & Gene Regulation”. As an IPP PhD student, you will join a community of exceptional scientists working on diverse topics ranging from how organisms age or how our DNA is repaired, to how epigenetics regulates cellular identity or neural memory. 

Activities and responsibilities

The research group of Thomas Hofmann offers the following PhD project:

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 Our unpublished results indicate an unforeseen link between loss of specific tumor suppressors, increased R-loop formation and genome instability.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.

Qualification profile:

Are you an ambitious, young scientist looking to push the boundaries of research while interacting with colleagues from multiple disciplines and cultures? Then joining the IPP is your opportunity to give your scientific career a flying start!

All you need is:

• Master or equivalent
• Interactive personality & good command of English
• 2 letters of reference

We offer

• Exciting, interdisciplinary projects in a lively international environment, with English as our working language
• Advanced training in scientific techniques and professional skills
• Access to our state-of-the-art Core Facilities and their technical expertise
• Fully funded positions with financing until the completion of your thesis
• A lively community of more than 200 PhD students from 44 different countries

For more details on the projects offered and how to apply via our online form, please visit  www.imb.de/phd .

The deadline for applications is 3 April 2025. Interviews will take place at IMB in Mainz on 23 & 24 June 2025.

Starting date: 1 August 2025 – 1 January 2026