My lab focuses on discovering functions of phosphorylation induced by damaged DNA in normal and cancer cells, and investigating the role of different phosphorylation events in cancer development.
MRE11 stability is regulated by CK2-dependent interaction with R2TP complex. Oncogene. Oncogene (2017) 36(34):4943-4950. PMID: 28436950
CK2-dependent PIH1D1 interactions define substrate specificity of the R2TP co-chaperone complex. Cell Rep (2014) 7: 19-26. PMID: 24656813
CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability. Mol Cell (2010) 39: 839-50. PMID: 20864032
DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature (2005) 434: 864-70. PMID: 15829956
My lab aims to identify novel protein interactions dependent on phosphorylation between DNA damage response proteins. We also aim to identify kinases, responsible for phosphorylation, and discover their precise function in the DNA damage response.
We hope that our work will bring deeper understanding of the DNA damage response, its regulation and interplay with other cellular processes. Understanding how DNA damage repair is carried out and regulated is essential for identification and further development of new and more efficient cancer treatments.
DNA is continually exposed to damaging agents such as UV light or products of cellular metabolism. Exposure to these agents can result in damage leading to harmful DNA mutations. Such mutations can deregulate cellular division and development and subsequently trigger transformation of normal cells into cancer cells. Cells therefore have DNA damage repair mechanisms, which are essential for their survival and act as an anti-cancer barrier.
The DNA repair mechanisms are controlled and regulated by phosphorylation signalling, which can activate or deactivate phosphorylated proteins or create or unique binding sites for other proteins. Mutations of kinases that carry out phosphorylation involved in DNA damage response or mutations of their target sites in DNA damage repair proteins are frequently found in tumours. At the same time drugs that inhibit enzymatic activity of the already known kinases regulating DNA damage response are already used as cancer chemotherapeutics.
Nuclear localisation of 53BP1 is regulated by phosphorylation of the nuclear localisation signal. von Morgen P, Lidak T, Horejsi Z et al. Biol Cell (2018) 110(2) 137-146
MRE11 stability is regulated by CK2-dependent interaction with R2TP complex. von Morgen P, Burdova K, Flower TG et al. Oncogene (2017) 36(2) 4943-4950
Assembly of the U5 snRNP component PRPF8 is controlled by the HSP90/R2TP chaperones. Malinová A, Cva¿ková Z, Mat¿j¿ D et al. J Cell Biol (2017) 216(2) 1579-1596
Human RIF1 and protein phosphatase 1 stimulate DNA replication origin licensing but suppress origin activation. Hiraga S-I, Ly T, Garzón J et al. EMBO Rep (2017) 18(2) 403-419
Substrate recognition and function of the R2TP complex in response to cellular stress. von Morgen P, Ho¿ejší Z, Macurek L Front Genet (2015) 6(2) 69
Phosphorylation-dependent PIH1D1 interactions define substrate specificity of the R2TP cochaperone complex. Ho¿ejší Z, Stach L, Flower TG et al. Cell Rep (2014) 7(2) 19-26
Tripartite Motif-containing 33 (TRIM33) protein functions in the poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response through interaction with Amplified in Liver Cancer 1 (ALC1) protein. Kulkarni A, Oza J, Yao M et al. J Biol Chem (2013) 288(2) 32357-32369
HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis. Adelman CA, Lolo RL, Birkbak NJ et al. Nature (2013) 502(2) 381-384
CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability. Horejsí Z, Takai H, Adelman CA et al. Mol Cell (2010) 39(2) 839-850
Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Adamo A, Collis SJ, Adelman CA et al. Mol Cell (2010) 39(2) 25-35