1. Research Background

The accurate replication and transmission of genetic material is of fundamental importance for cellular homeostasis and organism viability. Yet, cells are continually exposed to environmental and endogenous genotoxic agents that threaten DNA integrity. To protect their genomic stability, cells mount a complex network of DNA damage response pathways that activate cell cycle checkpoints, coordinate DNA repair, regulate gene expression and, if necessary, induce cell death. DNA damage signaling and repair is a powerful barrier to tumorigenesis, and defects in these pathways promote cell proliferation and genomic instability in premalignant lesions. Critically, genomic instability is also a driver of many aspects of cellular ageing and has been linked to the onset of age-associated diseases such as neurodegeneration and, of course, also cancer.

2. Research questions addressed by the group:

Our lab seeks to understand how cells detect, signal and repair DNA damage to protect genomic stability. Our lab focuses on the responses to diverse types of DNA lesions including bulky lesions, DNA double-strand breaks and replicative stress. In addition, we investigate how the DNA damage response intersects with the cellular pathways that maintain telomeric integrity. Potential PhD projects will revolve around one of the following two topics:

1. RNA-binding proteins and the DNA damage response. While many RNA- binding proteins have well-characterized roles in adjusting gene expression in response to genotoxic stress, it is becoming increasingly clear that these proteins also have non-canonical functions in the DNA damage response that go well beyond transcription, splicing and mRNA processing. Using cell biological and biochemical approaches, we aim to characterize such non-canonical RNA-binding protein functions at sites of DNA damage and at damaged chromatin to understand how RNA helps to facilitate the repair of DNA. In this context, a new project surrounding the RNA-binding protein TDP-43 will be discussed with interested applicants during the recruitment week and interview process.
2. DNA damage responses at telomeres. Somatic cells have finite replicative lifespans because telomeres undergo progressive shortening after DNA replication, which can lead to genome instability and induce senescence. Telomere dysfunction has profound physiological consequences and promotes the accelerated development of many age-associated pathologies such as tumorigenesis and kidney disease. In the context of this topic, new and exciting projects that aim to dissect the relationship of replication stress, DNA processing and telomere maintenance in vivo will be discussed with interested applicants

3. Applied Methods and model organisms:

We are an interdisciplinary lab that employs a wide range of molecular, genetic, cell biological and systems biology approaches. Applied methods include:

• State-of-the-art methods of molecular and cell biology (including molecular cloning as well as protein, DNA and RNA biochemistry)
• Advanced microscopy (including microlaser irradiation, live cell- and super-resolution microscopy)
• FACS
• Proteomics
• Cutting-edge CRISPR-Cas9-based genetics and screening

We work primarily with mammalian 2D and 3D tissue cultures. However, in the medium term, we will also work with mouse models of the DNA damage response.

4. Desirable skills and qualifications:

We seek an ambitious and pro-active student to join our new research team. Experience in mammalian tissue culture and omics approaches are desirable but not required. The student will receive extensive training in all relevant techniques.

5. References and key publications:

• Klaric, J.A., Wüst, S. and Panier, S. (2021). New faces of old friends: Emerging new roles of RNA-binding proteins in the DNA double-strand break response. Front Mol Biosci 8.
• Panier, S., Maric,M., Hewitt,G., Mason-Osann,E., Gali,H., Dai,A., Labadorf, A., Guervilly,J.H., Ruis,P., Segura-Bayona, S., Belan, O., Marzec,P., Gaillard,P.H.L., Flynn,R.L., Boulton,S.J. (2019) SLX4IP antagonizes promiscuous BLM activity during ALT maintenance.Mol Cell 76, 1-17.
• Panier, S., Ichijima, Y., Fradet-Turcotte, A., Leung, C.C., Kaustov, L., Arrowsmith, C.H., and Durocher, D. (2012). Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks. Mol Cell 47, 383-395.
• O'Donnell, L.*, Panier, S.*, Wildenhain, J.*, Tkach, J.M., Al-Hakim, A., Landry, M.C., Escribano-Diaz, C., Szilard, R.K., Young, J.T., Munro, M., et al. (2010). The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination. Mol Cell 40, 619-631. *co-first authors
• Stewart, G.S.*, Panier, S.*, Townsend, K., Al-Hakim, A.K., Kolas, N.K., Miller, E.S., Nakada, S., Ylanko, J., Olivarius, S., Mendez, M., et al. (2009). The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136, 420-434 *co-first authors
• Panier, S., and Boulton, S.J. (2014). Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol 15, 7-18.
• Panier, S.*, and Durocher, D.* (2013). Push back to respond better: regulatory inhibition of the DNA double-strand break response. Nat Rev Mol Cell Biol 14, 661-672. *co-corresponding authors