Laboratory of Molecular Genetics

Alexander I. Alexandrov
Ph.D. (Biology)
Head of Laboratory
INBI, build. 2, room 308
Телефон +7 (495) 954-40-97
E-Mail alexvir@inbi.ras.ru

Main achievements:

The most important achievements of the Laboratory of Molecular Genetics involve the study of prion and non-prion amyloids in the yeast Saccharomyces cerevisiae. We have demonstrated that the translation termination factor eRF3 manifests properties characteristic of the prion proteins of mammals.

We also identified the regions responsible for the prion properties and the translation termination activity of eRF3. Novel approaches to the analysis of prion particles structure were developed and the mechanism of their propagation and inheritance was suggested and supported by subsequent experiments. We have elucidated the role of the Hsp104 chaperone in yeast prion replication. The obtained data allowed us to define yeast prion as amyloids susceptible to fragmentation. The phenomenon of strain variability of yeast prions was demonstrated and studied and the molecular bases of prion interspecies transmission barriers were established.

We also have described the phenomenon of interdependence of amyloid formation, which allowed us to reveal the source of human huntingtin toxicity in yeast. Our group was the first to demonstrate that the yeast translation termination machinery is involved in controlling mRNA stability and also participates in the organization of the cytoskeleton and cell cycle regulation.

We have also identified and studied nonsense codon specific and non-specific modulators of translation termination efficiency.

A suite of the plasmid vectors and appropriate recipient strains of Hansenula polymorpha was created, which allowed molecular genetic studies with this yeast species. The behavior of replicative and integrative plasmids in H. polymorpha cells was studied. Particularly, recombinational rearrangements of transforming DNA were observed and characterized. The role of vesicular intracellular transport in maintaining Са2+ homeostasis was discovered and the relationship between the homeostasis of Са2+ ions and the control of cell cycle was revealed.

 

Selected publications:

  1.  Mitkevich, O. V., Kochneva-Pervukhova, N. V., Surina, E. R., Benevolensky, S. V., Kushnirov, V. V. and Ter-Avanesyan, M. D. (2012). DNA aptamers detecting generic amyloid epitopes. Prion 6, 400–406
  2. Alexandrov A.I., Polyanskaya A.B., Serpionov G.V., Ter-Avanesyan M.D., Kushnirov V.V. The effects of amino acid composition of glutamine-rich domains on amyloid formation and fragmentation// PLoS ONE. 2012. 7(10): e46458. doi:10.1371/journal.pone.0046458
  3. Kochneva-Pervukhova N.V., Alexandrov A.I., Ter-Avanesyan M.D. Amyloid-mediated sequestration of essential proteins contributes to mutant huntingtin toxicity in yeast// PLoS ONE. 2012. 7(1): e29832. doi:10.1371/journal.pone.0029832
  4. Alexandrov AI, Ter-Avanesyan MD. Could yeast prion domains originate from polyQ/N tracts?// Prion 2013; 7:209 – 214; doi:10.4161/pri.24628
  5. Agaphonov, M., Alexandrov, A. Self-excising integrative yeast plasmid vectors containing an intronated recombinase gene.// FEMS Yeast Research 2014. doi:10.1111/1567-1364.12197
  6. Nizhnikov, A., Alexandrov, A., Ryzhova, T., Mitkevich, O., Dergalev, A., Ter-Avanesyan, M., Galkin, A. Proteomic Screening for Amyloid Proteins.// PloS One 2014, 9(12), e116003. doi:10.1371/journal.pone.0116003
  7. Serpionov GV, Alexandrov AI, Antonenko YN, Ter-Avanesyan MD. A protein polymerization cascade mediates toxicity of non-pathological human huntingtin in yeast.// Sci Rep 2015; 5:18407
  8. Fokina, A. V., Chechenova, M. B., Karginov, A. V., Ter-Avanesyan, M. D. and Agaphonov, M. O. (2015). Genetic Evidence for the Role of the Vacuole in Supplying Secretory Organelles with Ca2+ in Hansenula polymorpha. PLoS One 10, e0145915
  9. Alexandrov AI, Serpionov GV, Kushnirov VV, Ter-Avanesyan MD. Wild type huntingtin toxicity in yeast: implications for the role of amyloid cross-seeding in polyQ diseases.// Prion 2016; 10(3):221-7; doi: 10.1080/19336896.2016.1176659
  10. Serpionov G V., Alexandrov AI, Ter-Avanesyan MD (2016) Distinct mechanisms of mutant huntingtin toxicity in different yeast strains. FEMS Yeast Research: fow102. doi:10.1093/femsyr/fow102.
  11. Urakov, V. N., Mitkevich, O. V, Safenkova, I. V and Ter-Avanesyan, M. D. (2017). Ribosome-bound Pub1 modulates stop codon decoding during translation termination  in yeast. FEBS J. 284, 1914–1930
  12. E Keinan, Ayelet-Chen Abraham , A Cohen , A Alexandrov, R Mintz , M Cohen, D Reichmann , D Kaganovich, Y Nahmias  (2018) High-Reynolds Microfluidic Sorting of Large Yeast Populations. Scientific Reports
  13. Anisimova, A.S., Alexandrov, A.I., Makarova, N.E., Gladyshev, V.N., and Dmitriev, S.E. (2018). Protein synthesis and quality control in aging. Aging (Albany. NY). 10, 4269–4288
  14. Karginov, A. V, Fokina, A. V, Kang, H. A., Kalebina, T. S., Sabirzyanova, T. A., Ter-Avanesyan, M. D. and Agaphonov, M. O. (2018). Dissection of differential vanadate sensitivity in two Ogataea species links protein glycosylation and phosphate transport regulation. Sci. Rep. 8, 16428
  15. Urakov, V. N., Mitkevich, O. V, Dergalev, A. A. and Ter-Avanesyan, M. D. (2018). The Pub1 and Upf1 Proteins Act in Concert to Protect Yeast from Toxicity of the [PSI(+)] Prion. Int. J. Mol. Sci. 19
  16. Alexandrov AI, Dergalev AA.  (2019). Increasing throughput of manual microscopy of cell suspensions using solid medium pads. MethodsX. Accepted for publication
  17. Alexandrov AI et al. (2019) Analysis of novel hyperosmotic shock response suggests “beads in liquid” cytosol structure. Препринт – https://www.biorxiv.org/content/10.1101/562728v1