R-loops are three-stranded nucleic acid structures consisting of an RNA-DNA hybrid and a displaced single-stranded DNA (Allison et al., CST 3, 38-46 (2019)). They form naturally during transcription, where they regulate gene expression, chromatin structure, and DNA repair (Allison et al., CST 3, 38-46 (2019); Fernandes et al., Cell Cycle 20, 1745-1759 (2021); Huang et al., Proc. Natl. Acad. Sci. U.S.A. 103, 5030-5035 (2006)). However, when improperly regulated, R-loops can lead to replication-transcription conflicts, DNA damage, and genome instability, contributing to diseases such as cancer and neurodegenerative disorders (Li et al., Cancers 15, 4986 (2023); Perego et al., Mol Neurobiol 56, 2579-2589 (2019)). Despite their physiological importance, the mechanisms by which R-loops induce genomic instability remain incompletely understood. 

DNA Polymerase theta (Polθ, encoded by the polq gene) is a predominant mediator of Polθ-mediated end joining (TMEJ) in most eukaryotes (Ramsden et al., Nat Rev Mol Cell Biol 23, 125-140 (2022)). While initially considered a backup pathway, recent studies suggest that TMEJ is a primary repair pathway in specific contexts, including replication stress, DNA damage in cancers cells, and immunoglobulin class-switch recombination (CSR) (Ceccaldi et al., Nature 518, 258-262 (2015); Roerink et al., Genome Res 24, 954-962 (2014); Yan et al., Nature 449, 478-482 (2023)). Intriguingly, many of these conditions are also associated with R-loop accumulation, raising the possibility that Polθ may play a direct role in repairing R-loop-induced damage. 

This study, conducted in Caenorhabditis elegans (C. elegans), will provide fundamental insights into how R-loops influence DNA repair pathway choice and contribute to genome instability. Our findings may also provide novel therapeutic strategies targeting R-loop-associated malignancies.

 

See also https://www.imb.de/wang 

For a more detailed description of the project including relevant literature, see here.

 

This PhD position is part of 4R Research Training Group (GRK2859) “R-loop Regulation in Robustness and Resilience (4R)”, funded by the German Research Foundation (DFG). 4R investigates how R-loops regulate biological processes across scales, from molecules to organisms. At the same time the mechanistic regulation of R-loops themselves is studied. As one of a cohort of 12 4R PhD positions, you will be part of a vibrant interdisciplinary research and training environment with specialized seminar series and tech talks and training courses that develop both scientific and complementary skills.

 

As a 4R-RTG PhD student, you will be integrated into the International PhD Programme (IPP; https://www.imb.de/phd), which is organized by IMB (www.imb.de). The IPP offers an exciting, interdisciplinary and lively international community of more than 200 PhD students from over 40 different countries. You will receive a broad range of support including supervision, training and career development opportunities.

We offer a stimulating, diverse and international research environment, with a pleasant working atmosphere, and informal culture. The institute is modern, well-equipped and centrally located with good public transport links and parking. Are you an ambitious scientist looking to push the boundaries of research while interacting with colleagues from multiple disciplines and cultures? Then joining the 4R-RTG and the IPP is your opportunity to give your scientific career a flying start!

To apply, please upload your application containing your cover letter stating research and career interests, CV, scans of your degrees (including copies of Abitur- and Master degree if existing), 2 reference letters to our application form on imb.de/jobs/scientific-positions. Should you have any questions regarding the application process, please contact us by email hr@imb-mainz.de, quoting Ref. No. #SWAPhD01. Informal enquires should be addressed to Dr Siyao Wang. IMB is an equal opportunity employer.