|Location:Home>Drug Discovery Pipeline>Core Technologies|
Dr. Strunnikov discovered the SMC (Structural Maintenance of Chromosomes) family of chromosomal proteins and made seminal contributions into other areas of chromatin research that have a direct relevance to cancer biology. These areas included: sister chromatin cohesion (cohesin complexes), mitotic chromosome condensation (condensin complex), centromere structure and function in yeast and human cells, mitotic segregation of nucleolar organizer/rDNA, regulation of chromatin functions by CDC14 and posttranslational modifications with SUMO, and genomics of chromosomal damage undetectable by checkpoints.
In the recent years, the advance of cancer genomics and its introduction into the practical healthcare has brought a boom in the new generation of drugs specifically targeting driver mutations in tumor-associated genes. However, sequencing of genomes of post-treatment relapse tumors strongly indicates that tumor driver mutations, which are targeted by most designer anticancer drugs, are late occurrences in tumor development. Furthermore, in-depth analyses of the growing number of cancer genomes also indicated that early events in tumorigenesis, such as epigenetic deregulation or chromothrypsis, represent universal molecular changes in all tumors. These changes in the epigenetic and genetic makeup of cancer cell provide a promising direction of research into universal therapeutic targets in cancers and into the causes of tumor relapses after currently available treatments.
New biomarkers for cancers
There are two main directions that are currently pursued at MEL with respect to biomarkers. The first focus area is on high-throughput approach to testing for cancer-testis antigens (CTAs). Second, MEL is developing a robust and time-efficient platform to test both genome an epigenome landmarks of different tumors in a high-throughput fashion.
Discovery of anticancer drug targets
Understanding the whole spectrum of deregulation of epigenetic controls in cancer is not possible without understanding the multifunctional nature of CTCF and its interacting factors. Targeting CTCF malfunction and CTCFL/BORIS activation in cancer using the toolbox of medicinal chemistry is the primary strategic goal of MEL. MEL is also engaged in assay development and in the validation of novel potential therapeutic targets among chromatin proteins.
Molecular mechanisms of cancer onset
MEL is also engaged in the research on pathway discovery in the epigenomics of chromosome instability in cancer. Massive breakage and rearrangement of chromosomes is one of the earliest events in cancer development, and MEL has established techniques to map chromosome breakpoints that are characteristic for a disruption of specific pathways controlling chromosome integrity, such as CIN genes as well as CT genes with a chromosome instability phenotype. The experimental modeling of these events characteristic for early oncogenesis aims to generate a compendium of chromosome instability patterns in human cancers.
Honors and awards
2016: “Chief Foreign Expert” Award, SAFEA China
2014: “Guangdong High Talent” Award, Guangdong Province, China
2012: “1000 Talents, State Specially Recruited Expert” Award, Government of China
2006: “Ten Years in Service to the Government of the United States of America”
2001: “Certificate of Recognition for Mentoring” from Howard Hughes Medical Institute
1999: “The NIH Director’s Series” Named Speaker
E. Pugacheva, E. Teplyakov, Q. Wu, J. Li, C. Chen, C. Meng, J. Liu, S. Robinson, D. Loukinov, A. Boukaba, A. P. Hutchins, V. Lobanenkov, A. Strunnikov (2016) The cancer-associated CTCFL/BORIS protein targets multiple classes of genomic repeats, with a distinct binding and functional preference for humanoid-specific SVA transposable elements. Epigenetics and Chromatin. In press.
K. Ohkuni, Y. Takahashi, A. Fulp, J. Lawrimore, W.C. Au, N. Pasupala, R. Levy-Myers, J.Warren, A. Strunnikov, R.E. Baker, O. Kerscher, K. Bloom, M.A. Basrai, (2016) SUMO-Targeted Ubiquitin Ligase (STUbL) Slx5 regulates proteolysis of centromeric histone H3 variant Cse4 and prevents its mislocalization to euchromatin. Molecular Biology of the Cell. 27:1500-1510.
E.M. Pugacheva, Rivero-Hinojosa S., Espinoza C.A., Méndez-Catalá C.F., Kang S., Suzuki T., Kosaka-Suzuki N., Robinson S., Nagarajan V., Ye Z., Boukaba A., Rasko J.E., Strunnikov A.V., Loukinov D., Ren B., Lobanenkov V.V. (2015) Comparative analyses of CTCF and BORIS occupancies uncover two distinct classes of CTCF binding genomic regions. Genome Biology.16:161.
A. Strunnikov (2013) Cohesin complexes with a potential to link mammalian meiosis to cancer. Cell Regeneration, 2:4
A. Samoshkin, S. Dulev, D. Loukinov, J.A. Rosenfeld, and A.V. Strunnikov (2012) Condensin dysfunction in human cells induces nonrandom chromosomal breaks in anaphase, with distinct patterns for both unique and repeated genomic regions. Chromosoma. 121:191-199.
A. Strunnikov (2010) One-hit wonders of genomic instability. Cell Division 5: 15
E. Pugacheva, T. Suzuki, S. Pack, N. Kosaka-Suzuki, J. Yoon, A. Vostrov, E. Barsov, A. Strunnikov, H. Morse III, D. Loukinov, V. Lobanenkov. (2010) The structural complexity of the human BORIS gene in gametogenesis and cancer. PLoS ONE 5:e13872
A. Samoshkin, A. Arnaoutov, L.E.T. Jansen, I. Ouispenski, L. Dye, T. Karpova, J. McNally, M. Dasso, Don W. Cleveland and A. Strunnikov. (2009) Human condensin function is essential for centromeric chromatin assembly and sister kinetochore orientation. PLoS ONE 4:e6831
S. Dulev, C. de Renty, R. Mehta, I. Minkov, E. Schwob and A. Strunnikov. (2009) Essential global role of CDC14 in DNA synthesis revealed by chromosome underreplication unrecognized by checkpoints in cdc14 mutants. PNAS 106: 14466-14471
Y. Takahashi, Iwase M, A. Strunnikov, Y. Kikuchi (2008) Cytoplasmic sumoylation by PIAS-type Siz1-SUMO ligase. Cell Cycle. 7:1738-1744
Y. Takahashi, S. Dulev, X. Liu, N. Hiller, X. Zhao and A. Strunnikov (2008) Cooperation of sumoylated chromosomal proteins in rDNA maintenance. PLoS Genetics 4:e1000215
S. Dulev, L. Aragon, and A. Strunnikov (2008) Unreplicated DNA in mitosis precludes condensin binding and chromosome condensation in S. cerevisae. Frontiers in Biosciences 13:5838-5846
Y. Takahashi and A. Strunnikov (2008) In vivo modeling of polysumoylation uncovers targeting of Topoisomerase II to the nucleolus via optimal level of SUMO modification. Chromosoma 117:189-198
B.D. Wang and A. Strunnikov (2008) Transcriptional homogenization of rDNA repeats in the episome-based nucleolus induces genome-wide changes in the chromosomal distribution of condensin. Plasmid 59:45-53
V. Yong-Gonzalez, B.D. Wang, P. Butylin, I. Ouspenski and A. Strunnikov (2007) Condensin function at centromere chromatin facilitates proper kinetochore tension and ensures correct mitotic segregation of sister chromatids. Genes to Cells 12:1075-1090
A. Strunnikov (2006) SMC complexes in bacterial chromosome condensation and segregation. Plasmid 55:135-144
B. D. Wang, P. Butylin and A. Strunnikov (2006) Condensin function in mitotic nucleolar segregation is regulated by rDNA transcription. Cell Cycle 5:2260-2267
Y. Takahashi, V. Yong-Gonzalez, Y. Kikuchi and A. Strunnikov (2006) The SIZ1/SIZ2 control of chromosome transmission fidelity is mediated by their role in sumoylation of topoisomerase II. Genetics 172:783-794
B. Quimby, V. Yong-Gonzalez, T. Anan, A. Strunnikov and M. Dasso (2006) The promyelocytic leukemia protein (PML) stimulates Sumo conjugation in yeast. Oncogene 25:2999-3005
A. Strunnikov. (2005) A case of selfish nucleolar segregation. Cell Cycle 4: 113-117
B.D. Wang, D. Eyre, M. Basrai, M. Lichten and A. Strunnikov (2005) Condensin binding at distinct and specific chromosomal sites in the Saccharomyces cerevisiae genome. Molecular and Cellular Biology 25: 7216-7225
B. D. Wang, V. Yong-Gonzalez and A. Strunnikov. (2004) Cdc14p/FEAR pathway controls segregation of nucleolus in S. cerevisiae by facilitating condensin targeting to rDNA chromatin in anaphase. Cell Cycle 3:960-967
A. Kagansky, L. Freeman, D. Lukyanov, and A. Strunnikov. (2004) Histone¬tail independent chromatin-binding activity of recombinant cohesin holocomplex. Journal of Biological Chemistry 279:3382-3388
A. Strunnikov. (2003) Condensin and biological role of chromosome condensation. Progress in Cell Cycle Research 5: 361-368
J. Mascarenhas, J. Soppa , A. Strunnikov and P. L. Graumann (2002) Cell cycle dependent localization of two novel prokaryotic chromosome segregation and condensation proteins in Bacillus subtilis that interact with SMC protein. EMBO Journal. 21:3108-3128
P. Meluh and A. V. Strunnikov (2002) Beyond the ABC of CKC and SCC. Do centromeres orchestrate sister chromatid cohesion or vice versa? European Journal of Biochemistry. 269:2300–2314
A. Strunnikov, L. Aravind and E. V. Koonin (2001) Saccharomyces cerevisiae SMT4 encodes an evolutionarily conserved protease with a role in chromosome condensation regulation. Genetics. 158: 95-107
L. Aragon-Alcaide and A. Strunnikov (2000) Functional dissection of in-vivo interchromosome association in S. cerevisiae. Nature Cell Biology 2: 812-818
L. Freeman, L.Aragon-Alcaide and A. Strunnikov (2000) The condensin complex governs chromosome condensation and mitotic transmission of rDNA. Journal of Cell Biology 149: 811-824
A. V. Strunnikov, R. Jessberger (1999) SMC Proteins: Conserved molecular properties for multiple biological functions. European Journal of Biochemistry. 263:6-13
N. Darwiche, L. A. Freeman , and A. Strunnikov (1999) Characterization of the components of the putative mammalian sister chromatid cohesion complex. Gene. 233:39-47
P. L. Graumann, R. Losick, A. V. Strunnikov (1998) Subcellular localization of Bacillus subtilis SMC, a protein involved in chromosome condensation and segregation. Journal of Bacteriology 180:5749-5755
A. V. Strunnikov (1998) SMC proteins and chromosome structure. Trends in Cell Biology. 8: 454-459
V. Guacci, D. Koshland, A.V. Strunnikov (1997) A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae. Cell 91:47-57
D. Koshland and, A. Strunnikov (1996) Mitotic chromosome condensation. Annual Reviews of Cell and Developmental Biology 12:305-333
Strunnikov, E. Hogan and D. Koshland (1995) SMC2,a Saccharomyces cerevisiae gene essential for chromosome segregation and condensation defines a subgroup within the SMC-family. Genes and Development 9: 87-599
Strunnikov, J. Kingsbury and D. Koshland (1995) CEP3 encodes a centromere protein of Saccharomyces cerevisiae. Journal of Cell Biology 128:749-760
Strunnikov, V. Larionov and D. Koshland (1993) SMC1: an essential yeast gene encoding a putative head-rod-tail protein is required for nuclear division and defines a new ubiquitous protein family. Journal of Cell Biology 123:1635-1648
Guacci, A. Yamamoto, A. Strunnikov, J. Kingsbury, E. Hogan, P. Meluh and
D. Koshland (1993) Structure and function of chromosomes in mitosis of budding yeast. In: Cold Spring Harbor Symposia on Quantitative Biology /DNA and Chromosomes. 58:677-685, Cold Spring Harbor, New York
V. Larionov, N. Kouprina N., A. Strunnikov and A. Vlasov (1989) A direct selection procedure for isolating yeast mutants with an impaired segregation of artificial minichromosomes. Current Genetics 15:17-26
V. Larionov, N. Kouprina, A. Strunnikov, A. Vlasov and V. Pirozhkov (1989) Direct selection procedure for isolation of yeast mutants with impaired segregation of chromosomes. Progress in Clinical and Biological Research, Vol. 138: Mechanisms of chromosome distribution and aneuploidy, 303-316; Alan R. Liss, Inc., New York
Dr.Alex Strunnikov receives the 1000 Talents Award from the PRC Minister of