Education: Kazan State University, Russia; M. S., Microbiology, 1989; Institute for Molecular Biology, University of Aarhus, Denmark; Institute of Cytology, Russian Academy of Sciences; Ph. D., Molecular and Cellular Biology, 1994
Reader, Department of Biochemistry, University of Leicester, UK; Head of Molecular Biology, Laboratory of Molecular Pharmacology of St Petersburg Institute of Technology (Technical University), Russia.
Reviewer for: Mol.& Cell Biol., Journal of Biological Chemistry, the EMBO Journal, Oncogene, Nature Structural &Mol. Biol.
Role of post-translational modifications in regulation of tumour suppressors.
Often DNA damage-response signalling pathway and/or DNA repair system fail to recognise and hence repair the damage. In this case, unrepaired cells are either blocked from dividing or targeted for physical elimination. Both these processes are controlled by tumour suppressor protein, p53. Perhaps, it is not surprising that p53 was found mutated in more than 50% of all human cancers. Accordingly, p53 is an appealing target for new therapeutic approaches.
The p53 tumour suppressor protein participates in cell cycle arrest and apoptosis chiefly as a sequence-specific transcription factor; it induces transcription of genes, whose products either block cell cycle progression (p21/WAF/Cip) or promote apoptosis (Puma, Bax, Noxa). Upon genotoxic stress, p53 undergoes massive post-translational modifications that change its conformation and interactions with other regulatory proteins, ultimately resulting in stabilisation and activation. Importantly, DNA damage facilitates acetylation of p53, which leads to its stabilization. On the contrary, under normal conditions, p53 undergoes ubiquitination, which target p53 for 26S proteasome-dependent degradation. Because acetylation and ubiquitination compete for the same lysine residues in p53, it will be important to find ways to activate acetylation and/or block ubiquitination to stabilize p53 and prevent cancer.
Currently, we are studying the physiological role of lysine methylation, acetylation and ubiquitination of p53 by various enzymes in vitro and in vivo. The long-term goal of our studies is to elucidate the role of post-translational modifications, especially ubiquitination and de-ubiquitination of p53 and to screen for small molecule inhibitors that would alter the modification state of p53.
Barlev, N. A., Emelyanov, A., Castagnino, P., Bannister, A., Birshtein, B., Kouzarides, T., and Berger, S. L. (2003) “Identification of a new homologue of yeast putative adaptor ADA2 in humans: novel mechanism of transcriptional co-activation” Mol. Cell. Biol, 23, pp. 6944-57.
Chuikov S., Kurash J.K., Wilson J.R., Xiao B., Justin N., Ivanov G.S., McKinney K., Tempst P., Prives C., Gamblin S.J., Barlev N.A.*, and Danny Reinberg* (2004) “Regulation of p53 activity through lysine methylation” Nature 432, pp.353-60. * co-corresponding author.
Morgunkova A., and Barlev N.A. (2006) “Lysine methylation goes global” Cell Cycle, 5, pp. 1308-12.
G. Ivanov, Ivanova, T., Kurash J.K, A. Ivanov, S. Chuikov, D. Proja, C. Kuperwasser, F. Rauscher, D. Reinberg, and N. A. Barlev (2007) " DNA damage activates p53 through a methylation-acetylation cascade" Mol. Cell. Biol, 27, pp. 6756-69.
A. G. Mittenberg, Tatyana N. Moiseeva, and N. A. Barlev (2008) “Role of proteasomes in transcription and their regulation by covalent modifications” Frontiers in Biosciences, 13, pp. 7184-92
O. A. Fedorova, T. N. Moiseeva, A. G. Mittenberg, , and N. A. Barlev (2010) “Recombinant proteasomal alpha-type subunits exhibit endoribonuclease activity” Tsitologiia, 52, pp. 1012-1015. (in Russian)
N. A. Barlev, B. S. Sayan, E. Candi, and A. L. Okorokov (2010) “The microRNA and p53 families join forces against cancer” Cell Death and Differentiation, 17 pp. 373-375.
V. A.Kulichkova, A. S.Tsimokha, O. A.Fedorova, T. N.Moiseeva, A. Bottril, L. Lezina, L. N. Gauze, I. M. Konstantinova, A. G. Mittenberg, and N. A. Barlev (2010) “26S proteasome exhibits endoribonuclease activity controlled by extra-cellular stimuli” Cell Cycle, 9 pp. 840-849.
T. N. Moiseeva, A. G. Mittenberg, and N. A. Barlev (2010) “Proteasomes and their role in transcriptional regulation” Tsitologiia, 52, pp. 195-203. (in Russian)
M. Khotin, L. Turoverova, V. Aksenova, N. Barlev, V. V. Borutinskaite, A .Vener, O. Bajenova, K. E. Magnusson, G. P. Pinaev, and D. Tentler (2010) “Proteomic analysis of ACTN4-interacting proteins reveals it's a putative involvement in mRNA metabolism” Biochemical and Biophysical Research Communications, 397, pp. 192-196.
C. T. Foster, O. M. Dovey, L. Lezina, J. L. Luo, T. W. Gant, N. Barlev, A. Bradley, and S. M. Cowley (2010) “Lysine-specific demethylase 1 regulates the embryonic transcriptome and CoREST stability” Mol Cell Biol, 30, pp. 4851-4863.
T. N. Moiseeva, O. A. Fedorova, A. S. Tsimokha, A. G. Mittenberg, and N. A. Barlev (2010) “Effect of ubiquitination on peptidase activities of proteasomes in genotoxic stress” Doklady Biochemistry and Biophysics, 435, pp. 307-311.
O. A. Fedorova, T. N. Moiseeva, A. A. Nikiforov, A. S. Tsimokha, V. A. Livinskaya, M. Hodson, A. Bottrill, I. N. Evteeva, J. B. Ermolayeva, I. M. Kuznetzova, K. K. Turoverov, I. Eperon, and N. A. Barlev (2011) “Proteomic analysis of the 20S proteasome (PSMA3)-interacting proteins reveals a functional link between the proteasome and mRNA metabolism” Biochemical and Biophysical Research Communications, 416, pp. 258-265.