Department of Functional Genomics
Alla V. Rynditch
Professor, Dr. Sci. (Mol. Biol.),
Education and Degrees:
1971 Ph.D. (biochemistry) Thesis: “Properties of DNA from nuclear polyhedrosis virus of silkworm”, O. V. Palladin Institute of Biochemistry, NASU, Kyiv, Ukraine
1990 Dr.Sci. (molecular biology). Thesis: “Structure and expression of Rous sarcoma virus in the cells of unrelative hosts”. Institute of Molecular Biology and Genetics (IMBG), NASU, Kyiv, Ukraine
1995 Professor (molecular biology), IMBG NASU
1995 Corresponding Member of NASU
1963–1964 Senior assistant, D. K. Zabolotny Institute of Microbiology and Virology (IMV), NASU, Kyiv, Ukraine
1964-1966 Trainee Researcher, IMV NASU, Kyiv, Ukraine
1966–1968 Junior Research Scientist, IMV NASU, Kyiv, Ukraine
1968–1977 Junior Research Scientist, IMBG NASU, Kyiv, Ukraine
1977–1986 Senior Research Scientist, IMBG NASU, Kyiv, Ukraine
1986–1989 Leading Research Scientist, IMBG NASU, Kyiv, Ukraine
1989–1992 Head of the Laboratory of Molecular Oncogenetics, IMBG NASU, Kyiv, Ukraine
since 1992 Head of the Department of Functional Genomics IMBG NASU, Kyiv, Ukraine
since 1989 Member of European Association for Cancer Research (EACR)
since 1991 Member of Human Genome Organisation (HUGO)
since 1994 Member of Committee of EACR
since 2005 Editorial Board member of Journal “Gene” (The Netherlands)
since 2009 Editorial Board member of Journal “Biopolymers and Cell” (Ukraine)
Honours, Prizes, Awards:
2004 Gershenson Award of National Academy of Sciences of Ukraine
The role of adaptor/scaffold proteins in the formation and regulation of multiprotein complexes during endocytosis, signal transduction, actin polymerization, viral infections and neuronal functioning
Regulation of gene expression at the level of alternative splicing
Identification and characterization of cancer–related genes
Ñurrent Research Activities and Recent Achievements:
Identification of novel functional interactions of intersectin (ITSN) family of adaptor/scaffold proteins.
Scaffolding proteins of ITSN family are crucial for the initiation stage of clathrin-mediated endocytosis. Moreover, they regulate actin cytoskeleton rearrangements, cell signalling and survival. Abnormalities of expression of ITSN1 gene, which is located on chromosome 21, are associated with the endocytic anomalies reported in patients with Down syndrome and Alzheimer’s disease. Our studies are focused on identification of novel ITSN interacting proteins and their functional significance, as well as determination of the mechanisms of posttranslational regulation of ITSN family. We have identified 11 novel protein partners of ITSN1 and ITSN2 implicated in endocytosis, cell signal transduction, actin cytoskeleton rearrangement and maintenance of virus latency. We have shown that latent membrane protein 2A (LMP2A) of Epstein–Barr virus forms a complex with ITSN1 and regulates its phosphorylation. ITSN2 was found to undergo tyrosine phosphorylation in a growth factor-dependent manner. Using Xenopus animal model we have demonstrated the role of ITSN2 in the coordinated changes of actin cytoskeleton during early embryonic development.
The role of alternative splicing in the modulation of functions of ITSN1.
We identified six novel splicing events of ITSN1 transcripts that do not introduce premature termination codon. Different combinations of these splicing events could generate 28 isoforms of ITSN1. The isoforms differ in their domain organization, interaction with protein partners, localization in different tissues and stages of development. The role of alternative splicing was clearly demonstrated in case of ITSN1 microexon 20 splicing that provides a mechanism for tissuespecific control of protein–protein interactions in neurons. Using mutational analysis we found that neuron-specific insertion of a microexon 20 leads to regulation of the SH3A domain specificity due to the shifting of negatively charged amino acids towards the interaction interface. Neuronspecific isoform of the SH3A domain binds with significantly higher affinity endocytic proteins dynamin 1 and synaptojanin 1, as well as GTPase-activating protein CdGAP, while the ubiquitously expressed isoform preferentially interacts with signalling proteins Sos1 and Cbl. We also detected the shortest ITSN1 isoform with an alternative C-terminus encoded by exon 22a. We demonstrated intramolecular binding within ITSN1- 22a that negatively regulates its association with the ubiquitin ligase Cbl.
Investigation of the role of ITSN1 in the synaptic transmission and plasticity.
We identified a stable tubule-only polypeptide (STOP) as an ITSN1-binding protein using affinity chromatography followed by MALDI-TOF mass spectrometry. STOP and ITSN1 were shown to form a complex in vivo and to partially colocalize in rat primary hippocampal neurons. STOP is a microtubule-stabilizing protein that is required for several forms of synaptic plasticity in the hippocampus. Identification of this interaction raises the possibility of ITSN1 participation in this process. Elucidation of the functional significance of ITSN1-STOP interaction in neurons is in progress.
Projects of National Academy of Sciences of Ukraine:
- 2012–2016 N 22.214.171.124 Project: “The role of proteinprotein interactions in normal physiology and pathological processes” (scientific supervisor – Alla Rynditch)
- 2012–2013 NASU and RFBR (Russian Foundation for Basic Research) N Ð1/2012 Project: “Identification and characterization of eukaryotic adaptor proteins which interact with transcriptional and chromatin remodeling complexes” (scientific supervisor – Alla Rynditch)
- 2010–2014 N 20/12 Project: “Production of nanoconjugates for high sensitive detection of biomarkers of early stages of neurodegenerative and oncological diseases in plasma” (scientific supervisor – Alla Rynditch)
- 2010–2014 N 37/12 Project: “Functional characterization of novel prognostic breast cancer marker ITSN2” of NASU (scientific supervisor – Alla Rynditch)
- 2010–2014 N 113/12-Í Project: “Development of high sensitive test system for Alzheimer’s disease neuronal markers detection in blood plasma using nanoconjugates” of NASU (scientific supervisor – Alla Rynditch) Projects of State Fund for Fundamental Researches:
- 2011–2013 State Key Laboratory of Molecular and Cell Biology N46/457 Project “Molecular mechanisms of cell signalling in normal and pathological conditions: the focus on ion channels”
- 2010–2013 N Ô33.4/001 Project: “Identification of perspective molecular biomarkers for monitoring neurodegenerative and oncological diseases of human” (scientific supervisor – M. À. Tukalo)
- 2011–2014 7th Framework Programme (FP7) FP7- INCO-2011-6, ERA-WIDE Project: “Strengthening cooperation in Molecular Biomedicine between EU and UKRAINE”, COMBIOM (scientific supervisor – Prof. A. Elskaya)
with Ukrainian organizations:
- O. V. Palladin Institute of Biochemistry, NASU (Kyiv)
- Bogomoletz Institute of Physiology, NASU (Kyiv)
- National University Lviv Polytechnic (Lviv)
- National Cancer Institute, Ministry of Health of Ukraine (Kyiv)
- State Institution “Institute of Urology of NAMS of Ukraine” (Kyiv)
with foreign organizations:
- Institute of Gene Biology, RAS (Moscow, Russia)
- Karolinska Institute (Stockholm, Sweden)
- Institute Jacques-Monod, CNRS (Paris, France)
- Institute Gustave-Roussy (Paris, France)
- Institute of Cellular and Integrative Neurosciences, CNRS (Strasbourg, France)
- International Institute of Molecular and Cell Biology (Warsaw, Poland)
- Dergai O., Dergai M., Rynditch A.V. Ubiquitin-ligase AIP4 controlsdifferentialubiquitinationandstability of isoforms of thescaffold protein ITSN1. FEBS Lett, Volume 592, Issue 13, 2259-2267
- GryaznovaT., Gubar O., Burdyniuk M., Kropyvko S., Rynditch A. WIP/ITSN1 complexisinvolvedincellularvesicletraffickingandformation of filopodia-likeprotrusions. Gene, 674, 49-56
- Dergai O., Cousin P., Gouge J ...Mechanism of selectiverecruitment of RNA polymerases II and III tosnRNAgenepromoters. Genes Development,32(9-10), 711-722
- Dobra I., Pankivskyi S., Samsonova A., Pastre D., Hamon L. Relation between stress granules and cytoplasmic protein aggregates linked to neurodegenerative diseases. Current Neurology and Neuroscience reports, 18, 107
- Svitina H., Kyryk V., Skrypkina ²., Kuchma V., Bukreieva T., Areshkov P. at all. Placenta derived multipotent cells have no effect on the size and number of DMH-induced colon tumors in rats. Experimental and Therapeutic Medicine, published online on: July 12, 2017 https://doi.org/10.3892/etm.2017.4792
- Völker JM, Dergai M, Abriata LA, Mingard Y, Ysselstein D, Krainc D, Dal Peraro, M von Mollard, GF Fasshauer, D Koliwer J, Schwake M. Functional assays for the assessment of the pathogenicity of variants in GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies. Dis Model Mech., 2017 Oct 5. pii: dmm.029132. doi: 10.1242/dmm.029132
- Gouge J., Guthertz N., Kramm K., Dergai O. at all. Molecular mechanisms of Bdp1 in TFIIIB assembly and RNA polymerase III transcription initiation. Nat Commun. 2017 Jul 25;8(1):130
- Kropyvko S., Gryaznova T., Morderer D., Rynditch A.V. Mammalian verprolin CR16 acts as a modulator of ITSN scaffold proteins association with actin. Biochem Biophys Res Commun, 2017 Mar 18;484(4):813-819. doi: 10.1016/j.bbrc.2017.01.177. Epub 2017 Feb 1.
- Skrypkina I., Tsyba L., Onyshchenko K., Morderer D., Kashparova O., Nikolaienko O., Panasenko G., Vozianov S., Romanenko A., Rynditch A. Concentration and methylation of cell-free DNA from blood plasma as diagnostic markers of renal cancer. Disease Markers, 2016, 2016:3693096. DOI: 10.1155/2016/3693096.
- Kropyvko S.V. Gubar O.S.. Gryaznova T.A Morderer D.Ye. Gerasymchuk D.O. Syvak L.À. Grabovoy A.N. Rynditch A.V. Transcriptional and post-transcriptional regulation of the adaptor/scaffold protein gene ITSN1. Biopolym. Cell. 2016, 32(3):202–226.
- Dergai M., Iershov A., Novokhatska O. Pankivskyi S. Rynditch A. Evolutionary Changes on the Way to Clathrin-Mediated Endocytosis in Animals. Genome Biol Evol., 2016 8(3): 588-606.
- Gouge J, Satia K, Guthertz N, Widya M, Thompson AJ, Cousin P, Dergai O, Hernandez N, Vannini A. Structural Basis of Redox Signaling by the RNA Polymerase III TFIIB-related Factor Brf2. Cell. 2016; 163(6):1375-1387.
- Gryaznova T, Kropyvko S, Burdyniuk M, Gubar O, Kryklyva V, Tsyba L, Rynditch AV. Intersectin adaptor proteins are associated with actin-regulating protein WIP in invadopodia. Cell Signaling. 2015; 27: 1499-1508.
- Morderer DYe, Nikolaienko OV, Rynditch AV. Identification of Ca2+/calmodulin-dependent phosphorylation sites of endocytic scaffold ITSN1 by tandem mass spectrometry. Biopolymers and Cell. 2015; 31(5):338-344.
- Morderer DYe, Nikolaienko OV, Skrypkina IYa, et al. Ca/calmodulin-dependent phosphorylation of endocytic scaffold ITSN1. Biopolymers and Cell. 2014;30(1):74-76.
- Bazalii A, Dvornikov D, Samoylenko A, et al. Interaction between adaptor proteins Ruk/CIN85 and Tks4 in normal and tumor cells of different tissue origins. Biopolymers and Cell. 2014;30(1):33-37.
- Tsyba L. O., Dergai M. V., Skrypkina I. Ya., et al. ITSN protein family: regulation of diversity, role in signalling and pathology. Biopolym. Cell. 2013; 29(3):244-251 doi: 10.7124/bc.00081E
- Dergai O, Dergai M, Skrypkina I, et al. The LMP2A protein of EpsteinBarr virus regulates phosphorylation of ITSN1 and Shb adaptors by tyrosine kinases. Cell Signal. 2013; 25(1): 33–40. doi:10.1016/j.cellsig.2012.09.011
- Morderer D, Nikolaienko O, Skrypkina I, et al. Endocytic adaptor protein intersectin 1 forms a complex with microtubule stabilizer STOP in neurons. Gene. 2012; 505(2):360–4.doi: 10.1016/j.gene.2012.06.061
- Novokhatska O, Dergai M, Houssin N, Tsyba L, Moreau J, Rynditch A. Intersectin 2 nucleotide exchange factor regulates Cdc42 activity during Xenopus early development. Biochem Biophys Res Commun. 2011; 408(4):663–8. doi: 10.1016/j.bbrc.2011.04.081
- Dergai M, Skrypkina I, Dergai O, et al. Identification and characterization of a novel mammalian isoform of the endocytic adaptor ITSN1. Gene. 2011; 485(2):120–9.doi:10.1016/j.gene.2011.06.021
- Tsyba L, Nikolaienko O, Dergai O, et al. Intersectin multidomain adaptor proteins: regulation of functional diversity. Gene. 2011; 473(2):67–75.doi:10.1016/j.gene.2010.11.016
- Kropyvko S, Gerasymchuk D, Skrypkina I, et al. Structural diversity and differential expression of novel human intersectin 1 isoforms. Mol Biol Rep. 2010; 37(6):2789–96. doi:10.1007/s11033-009-9824-8
- Nikolaienko O, Skrypkina I, Tsyba L, et al. Intersectin 1 forms a complex with adaptor protein Ruk/CIN85 in vivo independently of epidermal growth factor stimulation. Cell Signal. 2009; 21(5):753–9. doi: 10.1016/j.cellsig.2009.01.013
- Tsyba L, Gryaznova T, Dergai O, et al. Alternative splicing affecting the SH3A domain controls the binding properties of intersectin 1 in neurons. Biochem Biophys Res Commun. 2008; 372(4):929–34. doi:10.1016/j.bbrc.2008.05.156
- Kvasha S, Gordiyuk V, Kondratov A, et al. Hypermethylation of the 5'CpG island of the FHIT gene in clear cell renal carcinomas. Cancer Lett. 2008; 265(2):250–7. doi: 10.1016/j.canlet.2008.02.036
- Razin SV, Iarovaia OV, Sjakste N, et al. Chromatin domains and regulation of transcription. J Mol Biol. 2007; 369(3): 597–607.doi:10.1016/j.jmb.2007.04.003