Leroy F. Liu
Professor and Chairman
Department of Pharmacology
Robert Wood Johnson Medical School
B.S., National Taiwan University, 1971
Ph.D., University of California, Berkeley, 1977

Office: RWJMS/Piscataway R436
Telephone: (732) 235-4592
FAX: (732) 235-4073
E-mail: lliu@umdnj.edu

 

Tumorigenesis, topoisomerases, telomere regulation and senescence, DNA damage and repair.

Research Description:

Our main research interest is in the areas of cancer biology and cancer pharmacology. The following specific research projects are currently being conducted in this laboratory:
1. Studies on topoisomerase I-mediated DNA damage. Top I has been firmly established as a highly effective new molecular target for antitumor drugs such as camptothecins (CPTs) (e.g. irinotecan and topotecan). CPTs kill tumor cells by trapping a key covalent Top I-DNA reaction intermediate, the reversible cleavable complex. In addition to CPTs and other Top I-directed drugs, DNA structural modifications (e.g. benzo[a]pyrene-DNA adducts, UV adducts, oxidative modifications and AraC-substituted DNA) have been shown to cause trapping of Top I cleavable complexes. Despite the importance of Top I cleavable complexes as a new type of cellular lesion, our current understanding of repair/processing of Top I cleavable complexes is still quite limited. We have identified two novel molecular events downstream of the Top I cleavable complex, ubiquitin/26S proteasome-mediated degradation of Top I (Top I down-regulation) and SUMO-1 (small ubiquitin-related modifier) conjugation to Top I. The roles of these two novel pathways in the repair/processing of Top I cleavable complexes are being investigated.
2. Studies on topoisomerase II-mediated DNA damage. Top II-mediated DNA damage has been recognized as an important form of DNA lesion. Top II performs its function through its delicate act of breaking/rejoining DNA strands to resolve topological problems arising during DNA replication, transcription, and chromosome condensation and segregation. Because of its delicate act on DNA, Top II is highly vulnerable to xenobiotics (e.g. VP-16 and doxorubicin), DNA structural modifications (e.g. abasic sites) and cellular stresses (e.g. pH and thiol stresses). These insults abort the Top II reaction by trapping the reversible covalent Top II-DNA intermediate, termed the cleavable complexes. We are currently investigating the role of Top II-mediated DNA damage in the following three areas; (1) the role of transcription elongation and the ubiquitin/26S proteasome pathway in repair/processing of Top II cleavage complexes, (2) the role of Top II isozymes in ischemic acidosis and the nuclear-mitochondial signaling pathway leading to acidotic apoptosis, and (3) the role of Top II isozymes in tumorigenesis.
3. Studies on telomere-initiated senescence and apoptosis. Telomeres have been suggested to play a role in cellular senescence/aging and tumorigenesis. Telomere de-protection is known to trigger DNA damage/apoptotic signaling and cellular senescence. We have recently demonstrated that introduction of telomeric G-quartet DNA into cells triggers DNA damage/apoptotic signaling and cellular senescence. Moreover, overexpression of TRF-2 suppresses the effect of G-quartet DNA, suggesting that G-quartet DNA may play a role in telomere regulation and cellular senescence. We are currently testing the hypothesis that the regulated inter-conversion between the G-quartet DNA and the single-stranded G-tail DNA plays a major regulatory role in telomere maintenance and cellular senescence/cell death.

 

  Recent Publications:

 
  1. Makhey, D., Li, D., Zhao, B., Sim, S.-P., Li, T. K., Liu, A., Liu, L. F. and LaVoie, E. J. “Substituted Benzo[i]phenanthridines as Mammalian Topoisomerase-Targeting Agents” Bioorganic Med. Chem., 11:1809-1820 ( 2003)  
  2. Ruchelman, A. L., Singh, S. K., Ray, A., Wu, X. H., Yang, J.-M., Li, T. K., Liu, A., Liu, L. F., and LaVoie, E. J. “5H-Dibenzo[c,h]1,6-naphthyridin-6-ones: Novel Topoisomerase I-Targeting Anticancer Agents with Potent Cytotoxic Activity” Bioorganic Med. Chem., 11:2061-2073 (2003).  
  3. Yu, Y., Singh, S. K., Liu, A., Li, T.-K., Liu, L. F., and LaVoie, E. J. “Substituted Dibenzo[c,h]cinnolines: Topoisomerase I-Targeting Anticancer Agents” Bioorganic Med. Chem., 11:1475-1491 (2003).  
  4. Li, D., Zhao, B., Sim S.-P., Tsai-Kun Li, T.-K., Liu, A., Liu, L. F., and LaVoie, E. J. “2,3-Dimethoxybenzo[i]phenanthridines: Topoisomerase I-Targeting Anticancer Agents” Bioorganic Med. Chem.;11:521-528 (2003).  
  5. Nur-E-Kamal, A., Li, T.-K., Zhang, A, Qi, H., Hars, E. and Liu, L. F. “Single-stranded DNA induces ATM/p53-dependent DNA damage and apoptotic signals” J. Biol. Chem. 278:12475-12481 (2003).  
  6. Desai, S. D., Zhang, H., Rodriguez-Bauman, A., Yang, J.-M., Wu, X., Gounder, M. K., Rubin, E. H. and Liu, L. F. “Transcription-Dependent Degradation of Topoisomerase I-DNA Covalent Complexes” Mol. Cell. Biol. 23:2341-2350 (2003).  
  7. Xiao, H., Mao, Y., Desai, S. D., Zhou, N., Ting, C.-Y., Hwang, J. and Liu, L. F. “The Topoisomerase IIß Circular Clamp Arrests Transcription and Signals a 26S Proteasome Pathway” Proc. Natl. Acad. Sci. USA. 100:3239-3244 (2003).  
  8. Xiao, H., Li, T.-K., J.-M. Yang and Liu, L. F. “Acidic pH Induces Topoisomerase II-Mediated DNA Damage” Proc. Natl. Acad. Sci. USA. 100: 5205-5210 (2003).  
  9. Liu, L. F. “Degradation of Topoisomerase Cleavable Complexes” in DNA Topoisomerases in Cancer Therapy: Present and Future, Ed. Toshiwo Andoh, Kluwer Academic/Plenum Publishers, London UK. pp79-88 (2003).  
  10. Qi, H., Li, T.-K., Kuo, D., Nur-E-Kamal, A. and Liu, L. F. “Inactivation of Cdc13p triggers MEC1-dependent apoptotic signals in yeast” J. Biol. Chem. 278:15136-15141 (2003).  
  11. Zhou, N., Xiao, H., Nur-E-Kamal, A. and Liu, L. F. “DNA damage-mediated apoptosis induced by selenium compounds” J. Biol. Chem. 278:29532-29537 (2003).  
  12. Singh, S. K., Ruchelman, A. L., Li, T. K., Liu, A., Liu, L. F., and LaVoie, E. J. “Nitro and amino substitution in the D-ring of 5-(2-dimethylaminoethyl)- 2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-ones: effect on topoisomerase-I targeting activity and cytotoxicity”. J. Med. Chem. 46:2254-2257 (2003).  
  13. Li, D., Zhao, B., Sim, S. P., Li, T. K., Liu, A., Liu, L. F., and LaVoie, E. J. “8,9 -methylenedioxybenzo[i]phenanthridines: topoisomerase I-targeting activity and cytotoxicity”. Bioorg. Med. Chem. 11:3795-3805 (2003).  
  14. Li, T.-K., Desai, S. D., Daroui, P., Liu, A. A., Eszter S. Hars, Ruchelman, A. L., LaVoie, E. J. and Liu, L. F. “Characterization of ARC-111 as a Novel Topoisomerase I-Targeting Anticancer Drug” Cancer Res. 63:8400-8407 (2003).  
  15. Kerrigan J. E., Pilch, D.S., Ruchelman, A.L., Zhou, N, Liu, A., Liu, L., and LaVoie, E. J. “5H-8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h]naphthyridin-6-ones and related compounds as TOP1-Targeting agents: influence of structure on the ternary cleavable complex formation”. Bioorg. Med. Chem. Lett. 13:3395-3399 (2003).  
  16. Ting, C. Y., Hsu, C. T., Hsu, H. T., Su, J. S, Chen, T. Y., Tarn, W. Y., Kuo, Y. H., Whang-Peng, J., Liu, L. F., and Hwang, J. “Isodiospyrin as a novel human DNA topoisomerase I inhibitor”. Biochem. Pharmacol. 66:1981-1991 (2003).  
  17. Daroui, P., Desai, S. D., Li, T.-K., Liu, A. and Liu, L. F., “Hydrogen peroxide induces topoisomerase ?-mediated DNA damage and cell death”. J. Biol. Chem. 279(15):14587-14594 (2004).  
  18. Ruchelman, A. L., Singh, S. K., Ray, A., Wu, X., Yang, J. M., Zhou, N., Liu, A., and Liu, L. F., LaVoie, E. J. "11H-Isoquino[4,3-c]cinnolin-12-ones; novel anticancer agents with potent topoisomerase I-targeting activity and cytotoxicity". Bioorg Med Chem. 12:795-806 (2004).  
  19. Ruchelman, A. L., Kerrigan, J. E., Li, T. K., Zhou, N., Liu, A., Liu, L. F., and LaVoie, E. J. "Nitro and amino substitution within the A-ring of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: influence on topoisomerase I-targeting activity and cytotoxicity". Bioorg Med Chem. 12:3731-3742 (2004).  
  20. Nur-E-Kamal A, Gross SR, Pan Z, Balklava Z, Ma J, Liu LF. " Nuclear translocation of cytochrome c during apoptosis". J. Biol. Chem. 279:24911-24914 (2004).  
  21. Rajendra, R., Malegaonkar, D., Pungaliya, P., Marshall, H., Rasheed, Z., Brownell, J., and Liu, L. F., Lutzker, S., Saleem, A., and Rubin E. H. "Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53". J. Biol. Chem. 279(35):36440-36444 (2004).
  
  22. Ruchelman, A. L., Houghton, P. J., Zhou, N., Liu, A., Liu, L. F., and LaVoie, E. J. “5-(2-aminoethyl)dibenzo[c,h]napthyridin-6-ones:variation of N-alkyl substituents modulates sensitivity to efflux transporters associated with multidrug resistance”. J. Med. Chem. 48:792-804 (2005)  
  23. Qi, H., Li, T.-K., Kuo, D., Nur-E-Kamal, A. and Liu, L. F. “Inactivation of Cdc13p triggers MEC1-dependent apoptotic signals in yeast” J. Biol. Chem. in press (2003).  
  24. Nur-E-Kamal, A., Li, T.-K., Zhang, A, Qi, H., Hars, E. and Liu, L. F. “Single-stranded DNA induces ATM/p53-dependent DNA damage and apoptotic signals” J. Biol. Chem. in press (2003).  
  25. Desai, S. D., Zhang, H., Rodriguez-Bauman, A., Yang, J.-M., Wu, X., Gounder, M. K., Rubin, E. H. and Liu, L. F. “Transcription-Dependent Degradation of Topoisomerase I-DNA Covalent Complexes” Mol. Cell. Biol. In press (2003).  
  26. Xiao, H., Mao, Y., Desai, S. D., Zhou, N., Ting, C.-Y., Hwang, J. and Liu, L. F. “The Topoisomerase IIb Circular Clamp Arrests Transcription and Signals a 26S Proteasome Pathway” Proc. Natl. Acad. Sci. USA. In press (2003).  
  27. Xiao, H., Li, T.-K., Yang, J.-M. Yang and Liu, L. F. “Acidic pH Induced Topoisomerase II-Mediated DNA Damage” Proc. Natl. Acad. Sci. USA. In press (2003).  
     

 

  Lab Staff:    
  Anna Azarova

Graduate Student

  
  Rebecca Baerga Graduate Student  
  Stephen Chang Research Assistant  
  Parima Daroui Graduate Student  
  Shyamal Desai Assistant Professor  
  Xuan Fu Graduate Student  
  Eszter Hars Graduate Student  
  Chao-Po Lin Graduate Student  
  Haiyan Qi Assistant Professor  
  Alexandra Rodriguez Graduate Student  
  Lillia Ryazanov Research Teaching Specialist  
  Yuan-Chin Tsai Graduate Student  
  Lawrence Wood Graduate Student  
  Nai Zhou Graduate Student