MSNZ Projects

Burger Group

RNA-binding proteins (RBPs) and long non-coding (lnc)RNA are frequently deregulated in cancer and emerge as effectors of the DNA damage response (DDR). The non-POU domain-containing octamer-binding protein NONO/p54nrb and the non-coding nuclear enriched abundant transcript 1 (NEAT1) regulate gene expression within nuclear paraspeckles. Interestingly, the subcellular localisation of NONO and NEAT1 is responsive to DNA double-strand breaks (DSBs) and their depletion delays the DDR, suggesting a genome-protective role for paraspeckle components. We are interested in the RNA metabolic events that modulate the DNA damage response to promote genomic stability in healthy cells and drive tumorigenesis upon deregulation. In particular, we aim to

1. investigate the DNA damage response in crosstalk with nuclear bodies.

2. dissect the roles of NONO and NEAT1 in genome stability.

3. unravel novel effectors of RNA-dependent DSB repair.

Relevant Publications:

Ajit K, Alagia A, Burger K, Gullerova M (2024) Tyrosine 1 phosphorylated RNA polymerase II transcribes PROMPTs to promote proximal promoter pausing and induce global transcriptional repression in response to DNA damage. (2024) . Genome Res. accepted.

Trifault B, Mamontova V, Cossa G, Ganskih S, Wei Y, Hofstetter J, Bhandare P, Baluapuri A, Nieto B, Solvie D, Ade CP, Gallant P, Wolf E, Larsen DH, Munschauer M, Burger K. (2024) Nucleolar detention of NONO shields DNA double-strand breaks form aberrant transcripts. Nucleic Acids Res. doi: 10.1093/nar/gkae022

Trifault B, Mamontova V, Burger K. (2022) In vivo Proximity Labeling of Nuclear and Nucleolar Proteins by a Stably Expressed, DNA Damage-Responsive NONO-APEX2 Fusion Protein. Front Mol Biosci. doi: 10.3389/fmolb.2022.914873

Mamontova V, Trifault B, Burger K. (2022) Compartment-Specific Proximity Ligation Expands the Toolbox to Assess the Interactome of the Long Non-Coding RNA NEAT1. Int J Mol Sci. Review doi: 10.3390/ijms23084432

Mamontova V, Trifault B, Boten L, Burger K. (2021) Commuting to Work: Nucleolar Long Non-Coding RNA Control Ribosome Biogenesis from Near and Far. Noncoding RNA. Review doi: 10.3390/ncrna7030042

For more information about the MSNZ Würzburg click here.

Büchel Group

Amplification of MYCN is a driver and associated with high-risk cases of neuroblastoma. MYCN can be stabilized by complex formation with the Aurora-A kinase during S-phase. Previous work showed that treatment with the Aurora-A inhibitor MLN8237 is effective at high doses. In combinational with an ATR inhibitor, MLN8237 significantly improved the survival of mice harboring a neuroblastic tumor. The therapy engaged the immune system for tumor eradication. This involvement of the immune system opens new immunotherapeutic treatment options since neuroblastoma belong to the class of immunological unresponsive tumors.

In this project we are investigating how the tumor and the microenvironment, especially the immune system, react to inhibitors. We want to find out how we can use the immune system to attack the tumor.

Relevant Publications:

Büchel, G., Carstensen, A., Mak, K.Y., Roeschert, I., Leen, E., Sumara, O., Hofstetter, J., Herold, S., Kalb, J., Baluapuri, A., Poon, E., Kwok, C., Chesler, L., Maric H. M., Rickman, D. S., Wolf, E., Bayliss, R., Walz, S., Eilers, M. (2017) Association with Aurora-A controls N-MYC-dependent promoter escape and pause release of RNA polymerase II during cell cycle. Cell Reports Dec 19;21(12):3483-3497. doi:10.1016/j.celrep.2017.11.090.

Roeschert, I., Poon, E., Henssen, A.G., Dorado Garcia, H., Gatti, M., Giansanti, C., Jamin, Y., Ade, C.P., Gallant, P., Schülein-Völk, C., Beli, P., Richards, M., Rosenfeldt, M., Altmeyer, M., Anderson, J., Eggert, A., Dobbelstein, M., Bayliss, R., Chesler, L.*, Büchel, G.*, and Eilers, M.* (2021) Combined inhibition of Aurora-A and ATR kinases results in regression of MYCN-amplified neuroblastoma. Nat Cancer. https://doi.org/10.1038/s43018-020-00171-8

For more information about the MSNZ Würzburg click here.