Research Interest:
The expression of amplified genes is associated with the initiation and progression of cancers as well as the development of tumor cell resistance to anticancer drugs. A major goal of my laboratory is to determine the biochemical mechanism involved in gene amplification. We are testing the hypothesis that alterations in the synthesis of DNA intermediates required for DNA replication are early biochemical events that lead to the amplification of the oncogenes and certain drug resistance genes. Future studies are aimed at developing new therapies that can prevent the emergence of malignant and drug resistance phenotypes by blocking gene amplification. Specifically, we are testing the ability of fludarabine, an inhibitor of DNA replication, to block the amplification of the Mdr-1 and Pgp genes and prevent the subsequent development of drug resistance in patients having acute myelogeneous leukemia. DNA topoisomerases are enzymes that regulate the degree of DNA supercoiling in the cell. In a second major project we are testing the hypotheses that topoisomerase I and topoisomerase II poisons irreversibly damage DNA by inducing double-strand breaks in replication forks on the nuclear matrix. The cleaved replication forks then detach from the nuclear matrix, which induces DNA disorganization and apoptosis. Subsequent studies are aimed at identifying the cellular events that signal apoptosis and DNA repair following drug-induced damage to replicating DNA.
Positions: Director, Translational Research Shared Resource, Hollings Cancer Center, Medical University of South Carolina
Selected Publications:
| 1. | Salas A, Ponnusamy S, Senkal CE, Meyers-Needham M, Selvam SP, Saddoughi SA, Apohan E, Sentelle RD, Smith C, Gault CR, Obeid LM, El-Shewy HM, Oaks J, Santhanam R, Marcucci G, Baran Y, Mahajan S, Fernandes D, Stuart R, Perrotti D, Ogretmen B. Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A. Blood. .117(22):5941-52, 2011. PMCID: PMC3112039
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| | 2. | Tholanikunnel BG, Joseph K, Kandasamy K, Baldys A, Raymond JR, Luttrell LM, McDermott PJ, Fernandes DJ. Novel mechanisms in the regulation of G protein-coupled receptor trafficking to the plasma membrane. J Biol Chem. .285(44):33816-25, 2010. PMCID: PMC2962481
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| | 3. | Ishimaru D, Zuraw L, Ramalingam S, Sengupta TK, Bandyopadhyay S, Reuben A, Fernandes DJ, Spicer EK. Mechanism of regulation of bcl-2 mRNA by nucleolin and A+U-rich element-binding factor 1 (AUF1). J Biol Chem. .285(35):27182-91, 2010. PMCID: PMC2930717
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| | 4. | Vidyasagar MS, Kodali M, Prakash Saxena P, Upadhya D, Murali Krishna C, Vadhiraja BM, Fernandes DJ, Bola Sadashiva SR. Predictive and prognostic significance of glutathione levels and DNA damage in cervix cancer patients undergoing radiotherapy. Int J Radiat Oncol Biol Phys. .78(2):343-9, 2010.
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| | 5. | Ishimaru D, Ramalingam S, Sengupta TK, Bandyopadhyay S, Dellis S, Tholanikunnel BG, Fernandes DJ, Spicer EK. Regulation of Bcl-2 expression by HuR in HL60 leukemia cells and A431 carcinoma cells. Mol Cancer Res. .7(8):1354-66, 2009.
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| | 6. | Soundararajan S, Wang L, Sridharan V, Chen W, Courtenay-Luck N, Jones D, Spicer EK, Fernandes DJ. Plasma membrane nucleolin is a receptor for the anticancer aptamer AS1411 in MV4-11 leukemia cells. Mol Pharmacol. .76(5):984-91, 2009. PMCID: PMC2774992
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| | 7. | Gattoni-Celli S, Buckner CL, Lazarchick J, Stuart RK, Fernandes DJ. Overexpression of nucleolin in engrafted acute myelogenous leukemia cells. Am J Hematol. .84(8):535-8, 2009.
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| | 8. | Soundararajan S, Chen W, Spicer EK, Courtenay-Luck N, Fernandes DJ. The nucleolin targeting aptamer AS1411 destabilizes Bcl-2 messenger RNA in human breast cancer cells. Cancer Res. .68(7):2358-65, 2008.
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| | 9. | Otake Y, Soundararajan S, Sengupta TK, Kio EA, Smith JC, Pineda-Roman M, Stuart RK, Spicer EK, Fernandes DJ. Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA. Blood. .109(7):3069-75, 2007. PMCID: PMC1852223
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| | 10. | Otake Y, Mims A, Fernandes DJ. Merbarone induces activation of caspase-activated DNase and excision of chromosomal DNA loops from the nuclear matrix. Mol Pharmacol. .69(4):1477-85, 2006.
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| | 11. | Otake Y, Sengupta TK, Bandyopadhyay S, Spicer EK, Fernandes DJ. Retinoid-induced apoptosis in HL-60 cells is associated with nucleolin down-regulation and destabilization of Bcl-2 mRNA. Mol Pharmacol. .67(1):319-26, 2004.
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| | 12. | Otake Y, Sengupta TK, Bandyopadhyay S, Spicer EK, Fernandes DJ. Drug-induced destabilization of bcl-2 mRNA: a new approach for inducing apoptosis in tumor cells. Curr Opin Investig Drugs. .5(6):616-22, 2004.
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| | 13. | Sengupta TK, Bandyopadhyay S, Fernandes DJ, Spicer EK. Identification of nucleolin as an AU-rich element binding protein involved in bcl-2 mRNA stabilization. J Biol Chem. .279(12):10855-63, 2003.
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| | 14. | Bandyopadhyay S, Sengupta TK, Fernandes DJ, Spicer EK. Taxol- and okadaic acid-induced destabilization of bcl-2 mRNA is associated with decreased binding of proteins to a bcl-2 instability element. Biochem Pharmacol. .66(7):1151-62, 2003.
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| | 15. | Fernando LP, Kurian PJ, Fidan M, Fernandes DJ. Quantitation of gene-specific DNA damage by competitive PCR. Anal Biochem. .306(2):212-21, 2002.
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| | 16. | Carbone GM, Catapano CV, Fernandes DJ. Imbalanced DNA synthesis induced by cytosine arabinoside and fludarabine in human leukemia cells. Biochem Pharmacol. .62(1):101-10, 2001.
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| | 17. | Lambert JM, Fernandes DJ. Topoisomerase II cleavable complex formation within DNA loop domains. Biochem Pharmacol. .60(1):101-9, 2000.
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| | 18. | Catapano CV, Carbone GM, Pisani F, Qiu J, Fernandes DJ. Arrest of replication fork progression at sites of topoisomerase II-mediated DNA cleavage in human leukemia CEM cells incubated with VM-26. Biochemistry. .36(19):5739-48, 1997.
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| | 19. | Qiu J, Catapano CV, Fernandes DJ. Formation of topoisomerase II alpha complexes with nascent DNA is related to VM-26-induced cytotoxicity. Biochemistry. .35(50):16354-60, 1996.
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| | 20. | Catapano CV, Carbone GM, Fernandes DJ. The nuclear matrix as a target for cancer therapy. Ann Oncol. .7(7):659-66, 1996.
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| | 21. | Fleming RA, Capizzi RL, Muss HB, Smith S, Fernandes DJ, Homesley H, Loggie BW, Case L, Morris R, Russell GB, Richards F. Phase I study of N-(phosphonacetyl)-L-aspartate with fluorouracil and with or without dipyridamole in patients with advanced cancer. Clin Cancer Res. .2(7):1107-14, 1996.
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| | 22. | Yang JL, Fernandes DJ, Wheeler KT, Capizzi RL. PALA enhancement of bromodeoxyuridine incorporation into DNA increases radiation cytotoxicity to human ovarian adenocarcinoma cells. Int J Radiat Oncol Biol Phys. .34(5):1073-9, 1996.
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| | 23. | Lorico A, Rappa G, Srimatkandada S, Catapano CV, Fernandes DJ, Germino JF, Sartorelli AC. Increased rate of adenosine triphosphate-dependent etoposide (VP-16) efflux in a murine leukemia cell line overexpressing the multidrug resistance-associated protein (MRP) gene. Cancer Res. .55(19):4352-60, 1995.
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| | 24. | Catapano CV, Dayton JS, Mitchell BS, Fernandes DJ. GTP depletion induced by IMP dehydrogenase inhibitors blocks RNA-primed DNA synthesis. Mol Pharmacol. .47(5):948-55, 1995.
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| | 25. | Fernandes DJ, Catapano CV. The nuclear matrix as a site of anticancer drug action. Int Rev Cytol. .162A:539-76, 1995.
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| | 26. | Fernandes DJ, Qiu J, Catapano CV. DNA topoisomerase II isozymes involved in anticancer drug action and resistance. Adv Enzyme Regul. .35:265-81, 1995.
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| | 27. | Danks MK, Qiu J, Catapano CV, Schmidt CA, Beck WT, Fernandes DJ. Subcellular distribution of the alpha and beta topoisomerase II-DNA complexes stabilized by VM-26. Biochem Pharmacol. .48(9):1785-95, 1994.
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| | 28. | Catapano CV, Perrino FW, Fernandes DJ. Primer RNA chain termination induced by 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate. A mechanism of DNA synthesis inhibition. J Biol Chem. .268(10):7179-85, 1993.
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| | 29. | Fernandes DJ, Catapano CV. Nuclear matrix targets for anticancer agents. Cancer Cells. .3(4):134-40, 1991.
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| | 30. | Catapano CV, Chandler KB, Fernandes DJ. Inhibition of primer RNA formation in CCRF-CEM leukemia cells by fludarabine triphosphate. Cancer Res. .51(7):1829-35, 1991.
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| | 31. | Capizzi RL, White JC, Fernandes DJ. Antimetabolites. Baillieres Clin Haematol. .4(1):15-45, 1991.
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