Biology Department

Research Overview

Our research focus is on understanding the mechanisms of longevity and cancer resistance. Aging is the major cause of death in developed countries. By finding ways to delay aging it will be possible to delay the onset of multiple age-related diseases. Cancer is another major killer in developed world, where 25% of human mortality is caused by cancer. Cancer incidence increases exponentially with age and to achieve long-life species must evolve efficient tumor suppressor mechanisms. Our goal is to understand such mechanisms in mammalian species that are naturally cancer-resistant.

Anticancer mechanisms in the long-lived rodents the naked mole-rat and Eastern grey squirrel

Cancer affects most, if not all, classes of vertebrates. The major tumor suppressor pathway appear to be conserved among mammalian species, however, the cancer rates are strikingly different. For example, up to 95% of mice die from cancer, whereas another rodent, the naked mole rat appears to be cancer proof. Human cancer mortality is 25%, which is in somewhat in-between the mouse and the naked mole-rat. In addition to its cancer resistance naked mole-rat is highly interesting due to its longevity. It has the maximum lifespan of 30 years, which is almost 10 times longer than a similar size mouse. We recently discovered that the naked mole-rat has a novel anticancer mechanism named “early contact inhibition” that contribute to its cancer resistance. We are interested in the genes and signaling pathways involved in early contact inhibition and in other mechanisms that contribute to naked mole-rat longevity and cancer resistance. Eastern grey squirrel is another very interesting rodent. Grey squirrels are common in cities and parks across the United States, but a few people know that these rodents have a maximum lifespan of 24 years. Squirrels express extremely high telomerase activity in all tissues, comparable to human tumor tissue. High telomerase activity is generally associated with increased cancer risk, therefore squirrels must possess unique mechanisms that allow them to stay cancer free despite the high telomerase activity.

Sirtuins

Yeast Sir2 gene is a histone deacetylase involved in gene silencing. Furthermore overespression of Sir2 extends yeast lifespan and promotes genome stability. Mammals have seven homologs of Sir2 named sirtuins (SIRT1-SIRT7). Deletion of mouse SIRT6 leads to premature aging and genomic instability. We are interested in the role of SIRT6 in genome stability and stress resistance.

Anticancer mechanisms in whales

If all mammals were equally susceptible to oncogenic mutations and had equal tumor suppressor mechanisms one would expect that the rate of cancer would be proportional to the species body size and longevity. This is because greater number of cells and greater number of cell divisions would increase the chances of malignant transformation. Mammals range in body size from 30 g mouse to 110,000,000 g blue whale. If up to 95% of mice die of cancer by the age of 2 years it is paradoxical how come blue whales do not succumb to cancer in the womb. This fundamental question is named “Peto’s paradox” after Sir Richard Peto, who described it in 1975. The most plausible solution to Peto’s paradox is that the large and long-lived species have evolved superior anticancer systems. We are interested in understanding these mechanisms with the goal of using them to prevent human cancer.

Enumeration of anticancer mechanisms in mouse, human, and blue whale. These three species differ in body mass by a factor of 2,000: human is 2,000 times larger than a mouse, and blue whale is 2,000 times larger than a human. Humans have multiple additional anticancer adaptations compared to mice. It is currently unknown whether whales have evolved many additional anticancer adaptations compared to humans. Body mass in large whales is difficult to measure. Therefore, the figures are approximate estimates.

Peer Reviewed Publications

• Bochkareva, E., Seluanov, A., Bibi, E. and Girshovich, A. (1996) Chaperonin-promoted post-translational membrane insertion of a multispanning membrane protein lactose permease. J. Biol. Chem. 271(36), pp.22256-22261
• Seluanov, A. and Bibi, E. (1997) FtsY, the prokaryotic signal recognition particle receptor homologue, is essential for biogenesis of membrane proteins. J. Biol. Chem. 272(4), pp.2053-2055
• Zelazny, A., Seluanov, A., Cooper, A. and Bibi, E. (1997) The NG domain of the prokaryotic signal recognition particle receptor, FtsY, is fully functional when fused to an unrelated integral membrane polypeptide. Proc. Natl. Acad. Sci. USA 94(12), pp.6025-6029
• Seluanov* A., Herskovits* AA, Rajsbaum R, ten Hagen-Jongman CM, Henrichs T, Bochkareva ES, Phillips GJ, Probst FJ, Nakae T, Ehrmann M, Luirink J, Bibi E (2001) Evidence for coupling of membrane targeting and function of the signal recognition particle (SRP) receptor FtsY. EMBO Rep. 2(11), pp.1040-1046 * Equal contribution.
• Seluanov, A., Gorbunova, V., Falcovitz, A., Sigal, A., Milyavsky, M., Zurer., I., Shohat, G., Goldfinger, N. and V. Rotter (2001) Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53. Mol. Cell Biol., 21(5) pp.1552-1564.
• Gorbunova V. and A. Seluanov (2002) CLK-1 protein has DNA binding activity specific to OL region of mitochondrial DNA. FEBS Lett., 516(1-3) pp.279-284.
• Gorbunova V., Seluanov A., and O.M. Pereira-Smith (2002) Expression of hTERT protects normal human fibroblasts from stress-induced apoptosis and necrosis but does not prevent stress-induced premature senescence. J. Biol. Chem., 277(41) pp.38540-38549.
• Gorbunova, V., Seluanov, A., and O.M. Pereira-Smith (2003) Evidence that high telomerase activity may induce a senescent-like growth arrest in normal human fibroblasts. J. Biol. Chem., 278(9) pp.7692-7698.
• Gorbunova, V., Seluanov, A., Dion, V., Sandor, Z., Meservy, J.L., and J.H. Wilson (2003) Selectable system for monitoring the instability of CTG•CAG triplet repeats in mammalian cells. Mol. Cell Biol., 23(13) pp.4485-4493.
• Gorbunova, V., and Seluanov, A. (2003) Telomerase as a growth promoting factor. Cell Cycle., 2(6), pp.534-537.
• Seluanov*, A., Gorbunova*, V., Mittelman, D. and J.H. Wilson (2004) Genome-wide demethylation destabilizes CTG•CAG trinucleotide repeats in mammalian cells. Human Molecular Genetics., 13(23), pp.2979-2989. * Equal contribution.
• Seluanov, A., Mittelman, D., Pereira-Smith, O.M., Wilson, J.H., and V. Gorbunova (2004) DNA repair by nonhomologous end joining becomes less efficient and more error-prone during cellular senescence. Proc. Natl. Acad. Sci. USA., 101(20), pp.7624-7629.
• Gorbunova, V. and A. Seluanov (2005) Making ends meet in old age: DSB repair and aging., Mech. Aging. Dev., 126(6-7), pp.621-628. (Invited review)
• Shi X., Seluanov A., and V. Gorbunova (2007) Cell divisions are required for L1 retrotransposition. Mol. Cell. Biol., 27(4) pp.1264-1270.
• Seluanov A., Chen Z., Hine C., Sasahara T.H.C., Ribeiro A.A.C.M., Catania K.C., Presgraves D.C., and V. Gorbunova (2007) Telomerase Activity Coevolves with Body Mass not Lifespan., Aging Cell, 6(1) pp.45-52.
• Seluanov A., Danek J., and V. Gorbunova (2007) Changes in the level and distribution of Ku proteins during cellular senescence. DNA Repair (Amst), 6(12) pp.1740-1748.
• Mao Z., Seluanov A., Jiang Y., and V. Gorbunova (2007) TRF2 is required for repair of non-telomeric DNA double-strand breaks by homologous recombination, Proc. Natl. Acad. Sci. USA, 104(32) pp.13068-13073.
• Gorbunova V., Seluanov A., Mao Z., and C. Hine (2007) Changes in DNA repair during Aging. Nucleic Acids Res., 35(22) pp.7466-7474. (Invited review)
• Dion V., Lin Y., Price B.A., Fyffe S.L., Seluanov A., Gorbunova V., and J.H. Wilson (2008) Genome-wide demethylation promotes triplet repeat instability independently of homologous recombination. DNA Repair (Amst). 7(2) pp.313-320.
• Gorbunova V., Seluanov A. (2008) Rodents for comparative aging studies: from mice to beavers. Age, 30(2-3) pp.111-119. (Invited review) 21. Mao Z., Bozzella M., Seluanov A., and Gorbunova V. (2008) Comparison of nonhomologous end joining and homologous recombination in human cells. DNA Repair (Amst), 7(10) pp.1765-1771.
• Mao Z., Bozzella M., Seluanov A., and Gorbunova V. (2008) DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells. Cell Cycle, 7(18) pp.2902-2906.
• Seluanov A., Hine C., Bozzella M., Hall A., Sasahara T.H.C., Ribeiro A.A.C.M., Catania K.C., Presgraves D.C., and Gorbunova V. (2008) Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan. Aging Cell, 7(6) pp.813-823.
• Hine C., Seluanov A., and Gorbunova V. (2008) Use of Rad51 promoter for targeted anticancer therapy. Proc. Natl. Acad. Sci. USA, 105(52) pp.20810-20815
• Gorbunova V., Seluanov A. (2009) Coevolution of telomerase activity and body mass in mammals: from mice to beavers. Mech. Aging. Dev.,130(1-2):3-9 (Invited review)
• Mao Z., Jiang Y., Seluanov A., and Gorbunova V. (2009) DNA repair by homologous recombination, but not by nonhomologous end joining, is elevated in breast cancer cells. Neoplasia, 11(7):683-691
• Seluanov A., Hine C., Azpurua J., Feigenson M., Mao Z., Catania K.C., and Gorbunova V. (2009) Naked mole-rat cells are hypersensitive to contact inhibition – a clue to extraordinary cancer resistance. Proc. Natl. Acad. Sci. USA, 106(46):19352-19357*
  *Selected for Faculty of 1000 Medicine
  *Received Cozzarelli Prize as an exceptional paper published in 2009
• Seluanov A., Mao Z., and Gorbunova V. (2010) Analysis of DNA Double-Strand Break (DSB) Repair in Mammalian Cells. JoVE, In press
• Seluanov A., Vaidya A., and Gorbunova V. (2010) Establishing primary adult fibroblast cultures from rodents. JoVE, In press

Book Chapters

• Gorbunova V. and Seluanov A. (2009) A comparison of senescence in mouse and human cells, in “Senescence and Cancer”, Editors: Sedivy J. and Adams P., Springer

Patents

• Gorbunova V., Seluanov. A., and Hine C. (2008) Use of Rad51 promoter for transcriptionally targeted anticancer therapy. Invention disclosure # 6-1652, Pending.