Thymidylate synthase (TS) catalyzes the reductive methylation of dUMP to dTMP, a reaction that is essential for the de novo biosynthesis of dTTP for DNA replication and cell proliferation. Inhibitors of TS, such as the fluoropyrimidine antimetabolite 5-fluorouracil, have been important in the chemotherapy of cancer for quite some time, and remain a mainstay in the clinical management of neoplastic disease. A large body of research on TS and its inhibitors has led to detailed knowledge of the enzyme's structure (which governs its affinity for inhibitory ligands) and synthesis (which controls its intracellular concentrations). Recent studies by our group have identified new aspects of TS biology that will be important to further advances in the use of TS inhibitors for cancer treatment. The research program we propose in this application is a comprehensive one that focuses around several novel issues, including: the contribution of reactive oxygen species to the toxicity of TS inhibitors (AIM 1);post-translational modification of TS and regulation of its intracellular locale (AIM 2);and the function of nuclear TS in DNA repair and attenuation of genome damage (AIM 3). We suggest that response to TS inhibitors drugs depends upon the balance between ROS-dependent cell death and DNA repair-dependent cell survival. In all, this application proposes studies of newly recognized features of TS that should lead to novel insights into the role of this important drug target in cancer therapy.

Public Health Relevance

Thymidylate synthase (TS) has been an important target for anticancer chemotherapy for decades. The goal of the proposed project is to test the effects of modulating the levels of reactive oxygen species (ROS) on tumor response to TS inhibitors and examine the ability of FUra to potentiate the cytotoxicity of different classes of anti-neoplastic agents. The results of these studies will be valuable in developing new and novel therapies in combination with TS inhibitors that might synergize to enhance their anti-tumor efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044013-22
Application #
8267708
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
1990-03-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
22
Fiscal Year
2012
Total Cost
$178,930
Indirect Cost
$54,673
Name
University of South Carolina at Columbia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Barbour, Karen W; Xing, Yang-Yang; Pena, Edsel A et al. (2013) Characterization of the bipartite degron that regulates ubiquitin-independent degradation of thymidylate synthase. Biosci Rep 33:165-73
Zhang, Xinna; Wan, Guohui; Berger, Franklin G et al. (2011) The ATM kinase induces microRNA biogenesis in the DNA damage response. Mol Cell 41:371-83
Davis, Celestia; Price, Robert; Acharya, Grishma et al. (2011) Hematopoietic derived cell infiltration of the intestinal tumor microenvironment in Apc Min/+ mice. Microsc Microanal 17:528-39
Melo, Sandra P; Barbour, Karen W; Berger, Franklin G (2011) Cooperation between an intrinsically disordered region and a helical segment is required for ubiquitin-independent degradation by the proteasome. J Biol Chem 286:36559-67
Melo, Sandra P; Yoshida, Asami; Berger, Franklin G (2010) Functional dissection of the N-terminal degron of human thymidylate synthase. Biochem J 432:217-26
Pena, Maria Marjorette O; Melo, Sandra P; Xing, Yang-Yang et al. (2009) The intrinsically disordered N-terminal domain of thymidylate synthase targets the enzyme to the ubiquitin-independent proteasomal degradation pathway. J Biol Chem 284:31597-607
Barbour, Karen W; Berger, Franklin G (2008) Cell death in response to antimetabolites directed at thymidylate synthase. Cancer Chemother Pharmacol 61:189-201
Berger, F G; Kramer, D L; Porter, C W (2007) Polyamine metabolism and tumorigenesis in the Apc(Min/+) mouse. Biochem Soc Trans 35:336-9
Pena, Maria Marjorette O; Xing, Yang Yang; Koli, Sangita et al. (2006) Role of N-terminal residues in the ubiquitin-independent degradation of human thymidylate synthase. Biochem J 394:355-63
Berger, Sondra H; Berger, Franklin G; Lebioda, Lukasz (2004) Effects of ligand binding and conformational switching on intracellular stability of human thymidylate synthase. Biochim Biophys Acta 1696:15-22

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