Olga Mazin | Faculty Directory

Professional Background

Education

1996 - Ph.D - Biochemistry/Molecular Biology - Institute of Cytology & Genetics of the Russian Academy of Sciences, Novosibirsk. Advisor: Prof. Igor Zhimulev.
1979 - B. S. - Biochemistry/Molecular Biology - Novosibirsk State University, Russia

Training

2010 - Post-Doctoral Training - Department of Biochemistry and Molecular Biology - Drexel University College of Medicine, Philadelphia, PA Prof. Alexander Mazin)
2001 - Post-Doctoral Training - Section of Microbiology - University of California, Davis, California (Prof. Steven Kowalczykowski)
2000 - Post-Doctoral Training - Environmental Toxicology - Department of Environmental Toxicology (Prof. Fumio Matsumura), University of California, Davis, California
1997 - Post-Doctoral Training - Molecular and Cellular Biology - Department of Molecular and Cellular Biology (Prof. Kenneth Burtis) University of California

Highlights

Honors/Awards

1992 Institut National de la Sante et de la Recherche Medical (France) Research Fellowship Award

2003 Discovery day Award (Poster presentation, 3rd place) Drexel Univ.College of Medicine, Philadelphia, PA

2007 & 2008 Discovery day Award (Poster presentation, 2nd place) Drexel Univ. College of Medicine, Philadelphia, PA

2009 Discovery day Award (Poster presentation, 1st place) Drexel Univ. College of Medicine, Philadelphia, PA

Appointments

1980-1987 - Engineer, Senior Engineer - Laboratory of Enzymology (Dr Nina Pustoshilova). Applied Institute of Biological Active Substances. Berdsk, Russia
1987-1991 - Graduate student - Laboratory of Molecular Cytogenetics (Prof. Igor Zhimulev). Institute of Cytology and Genetics, Russian Academy of Sciences, Novosibirsk, Russia
1991-1992 - Visiting scholar - Laboratory of Developmental Biology (Dr. Jean-Antoine Lepesant), Institut Jacque Monod, Centre National de la Recherche Scientifique et Universite Paris 7, France
1994-2001 - Research assistant/Post-doctoral fellow - University of California, Davis, California 95616-8665, USA
2001-2010 - Post-doctoral fellow, Research Associate - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA
2010-2016 - Research Assistant Professor - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA
2016-2021 - Research Associate Professor - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA

Research & Grants

Grants

Contribution to Science:

I. Discovery of branch migration activity of Rad54 protein. In the process of homologous recombination in the cell, a four-stranded DNA intermediate called the Holliday junction arises. Holliday junctions can migrate along the DNA axis (branch migration) and its resolution or dissolution helps determine whether DNA recombinants with chromosome arm crossover or not are made. However, the identity of the proteins that catalyze branch migration of Holliday junctions in eukaryotes remained elusive for a long time. Our work has made major contributions in this area by showing that RAD54 is the branch migration motor in eukaryotes and determined regulatory mechanisms that underpin this RAD54 attribute. We demonstrated that during branch migration RAD54 can bypass regions of DNA heterology much more efficiently than BLM and RECQ1 helicases. In addition to promoting branch migration, RAD54 stimulates cleavage activity of Mus81/Eme1 resolvase that allows separation of joint molecules.

1. Bugreev, D. V., Mazina, O.M., and Mazin, A. V. (2006). Rad54 protein promotes branch migration of the Holliday junctions. Nature (London). v. 442: 590-593. PMID: 17545145. This article was rated by Faculty of 1000.

2. Mazina, O.M., Mazin, A.V. (2008) Human Rad54 protein stimulates human Mus81/Eme1 endonuclease. Proc. Natl. Acad. Sci. USA, 105(47): p. 18249-54. PMCID: PMC2587595

3. Mazina, O.M., Rossi, M.J., Deakyne, J.S., Huang, F., and Mazin, A.V. (2012). Polarity and bypass of DNA heterology during branch migration of Holliday junctions by human RAD54, BLM, and RECQ1. J. Biol. Chem. 287, 11820-11832. PMCID: PMC3320930

4. Goyal, N., Rossi, M.J., Mazina, O.M., Chi, Y., Moritz, R.L., Clurman B.E., Mazin A.V. (2018) RAD54 N-terminal domain is a DNA sensor that couples ATP hydrolysis with branch migration of Holliday junctions. Nature Comm., 9, article number 34, doi:10.1038/s41467-017-02497-x. PMCID: PMC5750232.

II. Understanding of the mechanism of branch migration by human RAD51. RAD51 recombinase has an ATPase activity. However, its role remained unclear, since it is not required for DNA strand exchange, the major RAD51 activity. We linked the RAD51 ATPase activity to the mechanism of branch migration promoted by this protein. We demonstrated that cycles of RAD51 polymerization and dissociation coupled with ATP hydrolysis drives branch migration of Holliday junctions. We demonstrated that this mechanism is conserved from bacterial RecA to human RAD51.

1. Rossi, M.J., Mazina, O.M., Bugreev, D.V., and Mazin, A.V. (2011). The RecA/RAD51 protein drives migration of Holliday junctions via polymerization on DNA. Proc Natl Acad Sci USA 108, 6432-6437. PMCID: PMC3080997

2. Bugreev, D.V., Huang, F., Mazina, O.M., Pezza, R.J., Voloshin, O.N., Daniel Camerini-Otero, R., and Mazin, A.V. (2014). HOP2-MND1 modulates RAD51 binding to nucleotides and DNA. Nature Com. 5, 4198. PMCID: 4279451

III. Study on the function of BLM helicase. Mutations in BLM helicase cause Bloom’s syndrome, a disorder characterized by genome instability and cancer predisposition. We have demonstrated that BLM functions by disrupting the Rad51-ssDNA filament, an active species in homologous recombination, and thereby preventing untimely initiation of homologous recombination. However, this disruption occurs only if RAD51 is present in an inactive ADP-bound form. When the RAD51-ssDNA is present in an active ATP-bound form, BLM stimulates DNA strand exchange activity of RAD51. Our results demonstrate the important role of the RAD51 nucleoprotein filament conformation in regulation of HR by BLM. Interestingly, the nucleoprotein filaments formed by DMC1, a meiosis specific RAD51 homolog, resist BLM disruption, which may account of the role of DMC1 in meiosis.

1. Bugreev, D.V., Mazina, O.M., and Mazin, A.V. (2009). Bloom syndrome helicase stimulates RAD51 DNA strand exchange activity through a novel mechanism. J. Biol. Chem. 284, 26349-26359. PMCID: PMC2786030

2. Bugreev, D. V., Pezza, R. J., Mazina, O. M., Voloshin, O. N., Camerini-Otero R. D., Mazin A. V. (2011) The resistance of DMC1 D-loops to dissociation may account for the DMC1 requirement in meiosis. Nature Struct. & Mol. Biol., 18, 56-60. PMCID: PMC3058924

IV. Studies on RNA-dependent DNA repair: a) Discovery of the inverse strand exchange activity of RAD52 and its role in RNA-templated DNA repair and b) R-loop formation activity of RPA. RNA can serve as a template for DNA double-strand break repair in yeast cells, and Rad52, a member of the homologous recombination pathway, plays role in this process. However, the exact mechanism of how Rad52 contributes to RNA-dependent DSB repair remained unknown. We discovered a novel activity of yeast and human Rad52: inverse strand exchange, in which Rad52 forms a complex with dsDNA and promotes strand exchange with homologous ssRNA or ssDNA. In accord with our in vitro results, our experiments in budding yeast provide evidence that Rad52-inverse strand exchange plays an important role in RNA-templated DSB repair in vivo.

1. Mazina, O.M., Keskin, H., Hanamshet, K., and Storici, F., Mazin, A.V., (2017) Rad52-inverse strand exchange drives RNA-templated DNA double-strand break repair. Molecular Cell, 67, p 19-29 3e. PMCID: PMC5547995.

Replication protein A (RPA), a major eukaryotic ssDNA-binding protein, is essential for all metabolic processes that involve ssDNA. While RPA is known to bind ssDNA tightly, it was presumed that it binds RNA weakly. However, recent data suggest that RPA may play a role in RNA metabolism. We investigated the RNA-binding properties of human RPA and found that RPA binds RNA with an unexpectedly high affinity (KD ≈ 100 pM). Furthermore, RPA by forming a complex with RNA can promote R-loop formation with homologous dsDNA. We showed that human DNA polymerases can utilize RPA-generated R-loops for initiation of DNA synthesis mimicking the process of replication restart in vivo. These results support the role of RPA in RNA metabolism and suggest a mechanism of genome maintenance that depends on RPA-mediated DNA replication restart.

1. Mazina, O.M., Somarowthu, S., Kadyrova, L.Y., Baranovskiy, A.G., Tahirov, T.H., Kadyrov, F.A., and A.V. Mazin (2020). Replication protein A binds RNA and promotes R-loop formation J. Biol. Chem., 295(41): p. 14203-14213 PMCID: PMC7549048

Publications

List of Publications, The asterisk (*) marks peer reviewed publications.

1. *Mazina O.M., Belyaeva E.S., Graphodatskaya V.E., Zhimulev I.F. (1990) Influence of the Drosophila melanogaster ecs locus on female fertility. // Genetika, 26:1038-1045.

2. *Mazina O.M., Dubrovsky E.B. (1990) The relationship between the female fertility function of the ecs locus and the gene for a minor chorion s70 protein of Drosophila melanogaster. // Genetika, 26:2156-2165.

3. *Mazina O.M., Belyaeva E.S., Zhimulev I.F. (1991) Cytogenetical analysis of the 2B3-4-2B11 region of the X-chromosome of Drosophila melanogaster. 7. Influence of the ecs locus on female fertility. // Molecular & General Genetics, 225:99-105.

4. *Mazina O.M., Korochkina S.E. (1991) Studies on the nature of female-sterile mutations at the ecs locus responsible for sensitivity to ecdysterone in Drosophila melanogaster. // Genetika, 27:1920-1927.

5. *Zhimulev I.F., Belyaeva E.S., Mazina O.M., Balasov M.L. (1995) Structure and expression of the br-c locus in Drosophila melanogaster. // European Journal of Entomology, 92:263-270.

6. *Mazin A.V., Timchenko T.V., Saparbaev M.K., Mazina O.M. (1996) Dimerization of plasmid DNA accelerates selection for antibiotic resistance. // Molecular Microbiology, 20:101-108.

7. *Harris P.V., Mazina O.M., Leonhardt E.A., Case R.B., Boyd J.B., Burtis K.C. (1996) Molecular cloning of Drosophila mus308, a gene involved in DNA cross-link repair with homology to prokaryotic DNA polymerase I genes. // Molecular and Cellular Biology, 16:5764-5771.

8. *Mazina O.M., Phillips M. A., Williams T., Vines C. A., Cherr G. N., Rice R. H. (2001) Dynamic localization of transcription factor AP-2 alpha in differentiating cultured human epidermal cells. // Journal of Investigative Dermatology, 117 (4): 864-870

9. *Mazina O, Park S, Sano H, Wong P, Matsumura F. (2004) Studies on the mechanism of rapid activation of protein tyrosine phosphorylation activities, particularly c-Src kinase, by TCDD in MCF10A. // J Biochem Mol Toxicol, 18 (6):313-21.

10. *Park S, Mazina O, Kitagawa A, Wong P, Matsumura F. (2004) TCDD causes suppression of growth and differentiation of MCF10A, human mammary epithelial cells by interfering with their insulin receptor signaling through c-Src kinase and ERK activation. // J Biochem Mol Toxicol, 18(6): 322-31.

11. *Mazina, O. M., Mazin, A. V., Nakagawa T., Kolodner R. D., and Kowalczykowski S. C. (2004). Saccharomyces cerevisiae Mer3 helicase stimulates 3’-5’ heteroduplex extension by Rad51: Implications for crossover control in meiotic recombination. // Cell, 117:47-56

12. *Mazina, O. M., and Mazin, A. V. (2004). Human Rad54 protein stimulates DNA strand exchange activity of hRad51 protein in the presence of Ca2+. // J. Biol. Chem. v. 279: 52041-52051. Selected by the JBC editors as a Paper of the Week (top 1-2% of JBC papers).

13. *Bugreev, D. V., Mazina, O.M., and Mazin, A. V. (2006).Analysis of branch migration activities of proteins using synthetic DNA substrates. // Nature Protocols, DOI: 10.1038/nprot.2006.217.

14. *Bugreev, D. V., Mazina, O.M., and Mazin, A. V. (2006). Rad54 protein promotes branch migration of the Holliday junctions. // Nature (London). v. 442: p.590-593 Faculty of 1000 Biology: evaluations for Bugreev DV et al Nature 2006 Aug 3 442 (7102) 590-3

http://www.f1000biology.com/article/id/1033843/evaluation

15. *Bugreev, D. V., Rossi, M. J., Mazina, O. M. and Mazin A V (2007). The Late Step of Homologous Recombination: Branch Migration of Holliday Junction. In: Molecular Genetics, Biophysics, and Medicine Today (Bresler Memorial Lectures), ed. V.A. Lanzov, PNPI Press, St. Petersburg/Gatchina, p. 141-158.

16. *Mazina, O. M., Rossi, M. J., Thoma, N., and Mazin A V (2007). Interactions of hRad54 protein with branched DNA molecules. // J. Biol. Chem., 282 (29): p. 21068-21080.

17. * Mazina, O.M., Mazin, A.V. (2008) Human Rad54 protein stimulates human Mus81/Eme1 endonuclease. // Proc. Natl. Acad. Sci. USA, 105 (47): p. 18249-54 (Truck II submission).

18, *Kumari, A., Mazina, O.M., Shinde, U., Mazin, A.V., and Lu, H. (2009). A role for SSRP1 in recombination-mediated DNA damage response. // J. Cell. Biochem., 108, p. 508-518.

19. *Bugreev, D.V., Mazina, O.M., and Mazin, A.V. (2009). Bloom syndrome helicase stimulates RAD51 DNA strand exchange activity through a novel mechanism. // J. Biol. Chem. 284, p. 26349-26359.

21.*Mazin, A.V., Mazina,O.M., Bugreev, D.V., Rossi.M.J. (2010) Rad54, the Motor of Homologous Recombination. Review Article.// DNA Repair (Amst), 9 (3), p. 286-302

22. *Rossi, M.J., Mazina, O.M., Bugreev, D.V., Mazin, A.V. (2010) Analyzing the branch migration activities of eukaryotic proteins. // Methods, 51(3), p. 336-46.

23. *Bugreev DV, Pezza RJ, Mazina OM, Voloshin ON, Camerini-Otero RD, Mazin AV.(2011) The resistance of DMC1 D-loops to dissociation may account for the DMC1 requirement in meiosis.// Nat Struct Mol Biol. 18 (1), p. 56-60.

24. *Rossi MJ, Mazina OM, Bugreev DV, Mazin AV. (2011) The RecA/RAD51 protein drives migration of Holliday junctions via polymerization on DNA. // Proc Natl Acad Sci U S A, 108 (16), p. 6432-7 (Truck II submission).

25. *Rossi MJ, Bugreev DV, Mazina OM, Mazin AV. (2011) Reconstituting the key steps of the DNA double-strand break repair in vitro. // Methods Mol Biol., 745, p. 407-20.

26. *Mazina OM, Rossi MJ, Deakyne JS, Huang F, Mazin AV. (2012) Polarity and bypass of DNA heterology during branch migration of Holliday junctions by human RAD54, BLM, and RECQ1 proteins. // J Biol Chem., 287(15), p. 11820-32.

27. *Huang F, Mazina OM, Zentner IJ, Cocklin S, Mazin AV. (2012) Inhibition of homologous recombination in human cells by targeting RAD51 recombinase.// J Med Chem., 55(7), p. 3011-20.

28. *Shahar OD, Kalousi A, Eini L, Fisher B, Weiss A, Darr J, Mazina O, Bramson S, Kupiec M, Eden A, Meshorer E, Mazin AV, Brino L, Goldberg M, Soutoglou E. (2014) A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair.// Nucleic Acids Res., 42(9), p. 5689-701.

29. *Bugreev DV, Huang F, Mazina OM, Pezza RJ, Voloshin ON, Camerini-Otero RD, Mazin AV. (2014) HOP2-MND1 modulates RAD51 binding to nucleotides and DNA.// Nat Commun., 5, p. 4198.

30. *Huang F, Goyal N, Sullivan K, Hanamshet K, Patel M, Mazina OM, Wang CX, An WF, Spoonamore J, Metkar S, Emmitte KA, Cocklin S, Skorski T, Mazin AV (2016) Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors.// Nucleic Acids Res., 44(9):4189-99.

31. *Hanamshet K, Mazina OM, Mazin AV. (2016) Reappearance from Obscurity: Mammalian Rad52 in Homologous Recombination.// Genes (Basel) 7(9):63.

32. *Mazina OM, Keskin H, Hanamshet K, Storici F, Mazin AV. (2017) Rad52 Inverse Strand Exchange Drives RNA-Templated DNA Double-Strand Break Repair.// Mol Cell, 67(1):19-29.

33. *Goyal N, Rossi MJ, Mazina OM, Chi Y, Moritz RL, Clurman BE, Mazin AV. (2018) RAD54 N-terminal domain is a DNA sensor that couples ATP hydrolysis with branch migration of Holliday junctions.// Nat Commun., 9(1):34.

34. *Mazina OM, Somarowthu S, Kadyrova LY, Baranovskiy AG, Tahirov TH, Kadyrov FA, Mazin AV. (2020) Replication protein A binds RNA and promotes R-loop formation.// J Biol Chem., 295(41):14203-14213.

35. *Meers C, Keskin H, Banyai G, Mazina O, Yang T, Gombolay AL, Mukherjee K, Kaparos EI, Newnam G, Mazin A, Storici F.(2020) Genetic Characterization of Three Distinct Mechanisms Supporting RNA-Driven DNA Repair and Modification Reveals Major Role of DNA Polymerase ζ.// Mol Cell, 79(6):1037-1050.

Book chapters:

1. Bugreev, D. V., Rossi, M. J., Mazina, O. M. and Mazin A V (2007). The Late Step of Homologous Recombination: Branch Migration of Holliday Junction. In: Molecular Genetics, Biophysics, and Medicine Today (Bresler Memorial Lectures), ed. V.A. Lanzov, PNPI Press, St. Petersburg/Gatchina, P. 141-158.

2. Mazin, A.V. and Mazina O. M., RAD51 is a key protein of homologous recombination in humans. In Advances DNA Repair in Cancer Therapy; eds L. Panasci, R. Aloyz, M. Alaoui-Jamali, 2nd Ed, Humana Press, 2012.

3. Mazin, A.V. and Mazina O. M., RAD51 and DMC1 recombinases. In Molecular Life Sciences. Springer Science + Business Media, New York, 2014.

4. Mazina OM, Mazin AV. (2018) Reconstituting the 4-Strand DNA Strand Exchange. Methods Enzymol., 600:285-305.

5. Mazina OM, Mazin AV. (2021) Branch Migration Activity of Rad54 Protein. Methods Mol Biol., 2153:145-167

Patents:

1. *Shulupin O.K., Fodor I.I., Serov G.D., Pustoshilova N.M., Mazina O.M., Selina A.V. Purification and characterization of a new restriction endonuclease XmaBI producing by Xanthomonas malvacearum strain B-2710 (Patent N 1152252, 22. 12. 1984., USSR).

Presentations

2008 Invited Speaker. Yokohama City University, Yokohama, Japan, “Rad54 protein stimulates human Mus81/Eme1 endonuclease.”
2008 Poster presentation. The 6th 3R Symposium. Tsumagoi Resort, Japan, “Interaction of the Bloom’s Syndrome Helicase with RAD51 recombinase”
2009 Invited participant. Cantoblanco Workshop on Molecular mechanism of genomic stability. Madrid, Spain, “Branch migration of Holliday junctions by human RAD51”.

Olga Mazin, PhD

Education

Training

Highlights

Appointments