Supervisor: Monika Gullerova

Eukaryotic cells employ a carefully coordinated network of signalling and repair proteins to resolve DNA damage, known as the DNA damage response (DDR). The most lethal form of DNA damage is double-stranded breaks (DSBs). Two key pathways in DSB repair are homologous recombination (HR) and non-homologous end joining (NHEJ). In HR, resection occurs at the break to expose ssDNA, allowing for homologous DNA to associate and act as a template for error-free repair. Contrastingly, NHEJ is error prone, involving digestion and ligation of the break, permitting the introduction of insertions and deletions.

Tudor Interacting Repair Regulator (TIRR), sits at the interface of HR and NHEJ. TIRR is well-established as an inhibitor of 53BP1 (1-4), an integral factor in promoting NHEJ. Upon the formation of DSBs, TIRR and 53BP1 dissociate, allowing recognition of chromatin (1). Interestingly, TIRR is a versatile mRNA binding protein (2,5,6). TIRR is also amplified across various cancer cell lines. We have found that kidney cancer cells are highly sensitive to TIRR depletion, which makes it an excellent clinical target.

In this project, we aim to understand the molecular mechanism behind TIRR sensitivity in kidney cancer. We will employ array of molecular techniques to investigate the role of TIRR in normal and kidney cancer cells. Data obtained from this project will have translational potential, which will be explored further.

Relevant publications

1. Drane, P., Brault, M.E., Cui, G., Meghani, K., Chaubey, S., Detappe, A., Parnandi, N., He, Y., Zheng, X.F., Botuyan, M.V. et al. (2017) TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature, 543, 211-216.
2. Ketley, R.F., Battistini, F., Alagia, A., Mondielli, C., Iehl, F., Balikci, E., Huber, K.V.M., Orozco, M. and Gullerova, M. (2022) DNA double-strand break-derived RNA drives TIRR/53BP1 complex dissociation. Cell Rep, 41, 111526.
3. Botuyan, M.V., Cui, G., Drane, P., Oliveira, C., Detappe, A., Brault, M.E., Parnandi, N., Chaubey, S., Thompson, J.R., Bragantini, B. et al. (2018) Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein. Nat Struct Mol Biol, 25, 591-600.
4. Dai, Y., Zhang, A., Shan, S., Gong, Z. and Zhou, Z. (2018) Structural basis for recognition of 53BP1 tandem Tudor domain by TIRR. Nat Commun, 9, 2123.
5. Avolio, R., Jarvelin, A.I., Mohammed, S., Agliarulo, I., Condelli, V., Zoppoli, P., Calice, G., Sarnataro, D., Bechara, E., Tartaglia, G.G. et al. (2018) Protein Syndesmos is a novel RNA-binding protein that regulates primary cilia formation. Nucleic Acids Res, 46, 12067-12086.
6. He, C., Sidoli, S., Warneford-Thomson, R., Tatomer, D.C., Wilusz, J.E., Garcia, B.A. and Bonasio, R. (2016) High-Resolution Mapping of RNA-Binding Regions in the Nuclear Proteome of Embryonic Stem Cells. Mol Cell, 64, 416-430.