The long-term goal of this project is to understand the fundamental molecular mechanism of tumor cell killing by topoisomerase I (Top I)-directed anticancer drugs. Top I has been firmly established as a highly effective new molecular target for 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 also 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. Our preliminary studies 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. Our studies have suggested that Top I down-regulation is triggered by arrest of the RNA polymerase elongation complex. In this application, we propose to determine the molecular mechanism through which transcriptional arrest triggers Top I down-regulation and p53-dependent apoptosis. The function of SUMO-1 conjugation to Top I cleavable complexes is still unclear, but has been suggested to modulate the lethal action of Top I cleavable complexes. In view of the potential importance of both of these novel responses in modulating tumor cell killing by Top I-directed anticancer drugs, we plan to elucidate their mechanism and function with the following specific aims: (1) to establish the role of transcription in the processing of CPT-induced Top I cleavable complexes, and (2) to characterize the SUMO-1-Top I conjugation reaction in response to CPT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA039662-21S1
Application #
7174154
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Ogunbiyi, Peter
Project Start
1985-04-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
21
Fiscal Year
2006
Total Cost
$47,463
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Lin, Ren-Kuo; Ho, Chia-Wen; Liu, Leroy F et al. (2013) Topoisomerase II? deficiency enhances camptothecin-induced apoptosis. J Biol Chem 288:7182-92
Ban, Yi; Ho, Chia-Wen; Lin, Ren-Kuo et al. (2013) Activation of a novel ubiquitin-independent proteasome pathway when RNA polymerase II encounters a protein roadblock. Mol Cell Biol 33:4008-16
Chiang, Hsiao-Ling; Lin, Chi-Yu; Jan, Fan-Dan et al. (2012) A novel synthetic bipartite carrier protein for developing glycotope-based vaccines. Vaccine 30:7573-81
Su, Yee-Fun; Yang, Tsunghan; Huang, Hoting et al. (2012) Phosphorylation of Ubc9 by Cdk1 enhances SUMOylation activity. PLoS One 7:e34250
Wan, Shan; Pestka, Sidney; Jubin, Ronald G et al. (2012) Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. PLoS One 7:e32542
Tsai, Yu-Chen; Pestka, Sidney; Wang, Lu-Hai et al. (2011) Interferon-? signaling contributes to Ras transformation. PLoS One 6:e24291
Lin, Ren-Kuo; Zhou, Nai; Lyu, Yi Lisa et al. (2011) Dietary isothiocyanate-induced apoptosis via thiol modification of DNA topoisomerase II?. J Biol Chem 286:33591-600
Feng, Wei; Satyanarayana, Mavurapu; Tsai, Yuan-Chin et al. (2009) Novel topoisomerase I-targeting antitumor agents synthesized from the N,N,N-trimethylammonium derivative of ARC-111, 5H-2,3-dimethoxy-8,9-methylenedioxy-5-[(2-N,N,N-trimethylammonium)ethyl]dibenzo[c,h][1,6]naphthyridin-6-one iodide. Eur J Med Chem 44:3433-8
Sharma, Lisa; Tsai, Yuan-Chin; Liu, Angela A et al. (2009) Cytotoxicity and TOP1-targeting activity of 8- and 9-amino derivatives of 5-butyl- and 5-(2-N,N-dimethylamino)ethyl-5H-dibenzo[c,h][1,6]naphthyridin-6-ones. Eur J Med Chem 44:1471-6
Lin, Chao-Po; Ban, Yi; Lyu, Yi Lisa et al. (2009) Proteasome-dependent processing of topoisomerase I-DNA adducts into DNA double strand breaks at arrested replication forks. J Biol Chem 284:28084-92

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