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. We are particularly interested in identifying and characterizing new regulators of the DNA damage response. Potential PhD projects will revolve around one of the following two aims:
- a) 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 identify and characterize such non-canonical RNA-binding protein functions at sites of DNA damage and at damaged chromatin.
- b) The DNA damage response does not consist of insulated signaling and repair pathways whose activities are restricted solely to the nucleus and to DNA damage sites. Instead, these pathways affect and are affected by very many other aspects of cell biology inside and outside of the nucleus, in particular cell metabolism. By combining genomic, metabolomic and cell biological approaches, we aim to understand how DNA damage response pathways such as the response to DNA double-strand breaks cross-talk with cell metabolic pathways and also how they respond to changing microenvironmental cues.
Specific projects will be discussed with interested applicants during the recruitment week and interview process.
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)
- Proteomics and metabolomics
- 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