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Faculty Detail    
Campus Address VH 155 Zip 0019
Phone  (20-5) -572
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Undergraduate  H.L.O. Delft, The Netherlands    1990  B.Sc. Biothechnology 
Graduate  University of Groningen, The Netherlands    1992  M.Sc. Biotechnology 
Graduate  University of Groningen, The Netherlands    1997  Ph.D. Medical Oncology 

Faculty Appointment(s)
Appointment Type Department Division Rank
Primary  Pharmacology/Toxicology   Pharmacology/Toxicology Chair's Office Associate Professor
Center  Comprehensive Cancer Center  Comprehensive Cancer Center Associate Professor

Graduate Biomedical Sciences Affiliations
Biochemistry and Structural Biology 
Cancer Biology 
Medical Scientist Training Program 
Pathobiology and Molecular Medicine 

Biographical Sketch 
After a post-doctoral fellowship at the Netherlands Cancer Institute (department of Experiment Therapy) were I resolve the mechanism of synergistic toxicity between platinum agents and DNA topoisomerase I inhibitors, and was part of the team that discovered that ABC transporter/Drug efflux pump BCRP (Breast Cancer Related Protein) is involved in removing topotecan from the cellular compartment, I came to St. Jude Children's Research Hospital department of Molecular Pharmacology for a second post-doctoral fellowship. We resolved the structure of yeast Ubc9 (the SUMO E2-conjugating Enzyme) and performed structure-function analysis of yeast and human UBC9 in relationship to DNA damage response/repair. in addition, I started working of Tyrosyl-DNA phosphodieasterase I (Tdp1) structure-function analysis.

Society Memberships
Organization Name Position Held Org Link
American Association for Cancer Research     
The American Society for Biochemistry and Molecular Biology     

Research/Clinical Interest
Structure-Function analysis of Tyrosyl-DNA phosphodieasterase I; Developing a DNA Repair Enzyme as Therapeutic Target for Anti-Cancer Treatment
Research Interest: We are interested in the response of cells to treatment with chemotherapeutics, specifically DNA damaging agents. To investigate this response, we use yeast genetics, biochemistry, and RNAi technology in human cells, and collaborate with Structural Biologists to analyze the structure-function relations and mechanisms of action of proteins and anti-cancer drugs. The lab studies the eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1), which belongs to the phospholipase D superfamily. Tdp1 comprises a very interesting catalytic cycle that consists of two active site histidines, one that functions as nucleophile and the other one as general acid/base. Using this histidine couple, Tdp1 is able to remove DNA adducts from the 3’- and 5’-end of a DNA strand break. The interaction between Tdp1 and its substrates needs to be very adaptable since Tdp1 hydrolyses a wide variety of substrates that differ in size and complexity, e.g. from a small and simple damage nucleotide to a large and complex protein-DNA adduct. We use two clinically relevant model substrates; DNA topoisomerase I (Top1) to study 3’DNA-adducts and DNA topoisomerase II (Top2) for 5’ DNA- adducts. Using these substrates, we are able to study Tdp1 function in vivo/cell. We are interested in the structure-function analysis of catalytic residue substitutions to investigate their catalytic function, determine mechanism of action (induction of cellular toxicity), and study Tdp1 cellular function/interaction with substrates and other proteins. In addition, we study the effects of post-translational modification, such as SUMOylation (SUMO conjugation), of Tdp1 on catalytic activity and protein-protein interactions, in both the yeast and human cell model. These studies will reveal Tdp1 physiological function, and identified Tdp1 as a therapeutic target for drug studies, which are ongoing in the lab and are in part supported by the Alabama Drug Discovery Alliance (ADDA). Besides DNA repair, Tdp1 is also involved in neurodegeneration, as a substitution of the general acid/base histidine to arginine was identified in patients with the autosomal recessive disease spinocerebellar ataxia with axonal neuropathy (SCAN1). The mechanism by which this substitution only affects cerebellar neuronal cells is unknown. We are interested in elucidating this interesting phenotype by studying the role of Tdp1 in genome stability. Interestingly, these SCAN1 patients are not prone to other genetic disease, such as cancer or immune-deficiencies, suggesting that the cellular conditions of these cerebellar neurons play an important role in disease development Another subject the lab is interested in is the role of post-translational modification of proteins by ubiquitin and ubiquitin-like proteins, specifically SUMO (small ubiquitin-like modifier) in response to DNA damage. We focus on the effects of SUMOylation of proteins stimulated by SUMO E3-ligase and the effects of SUMO modification on protein-protein. Unlike the ubiquitin pathway, the SUMO pathway only uses a limited amount (10 to 20) of E3-ligases, which specifically stimulates SUMO conjugation to a sub-set of proteins (substrates). We are interested in identifying those proteins that are modified and play a role in the response to DNA damage in human cells.

Selected Publications 
Publication PUBMEDID
van Waardenburg RCAM, de Jong LA, van Delft F, van Eijndhoven MAJ, Bohlander M, Bjornsti M-A, Brouwer J, Schellens JHM. Homologous recombination is a highly conserved determinant of the synergistic cytotoxicity between cisplatin and DNA topoisomerase I poisons. Mol Cancer Ther 3(4):393-402, 2004  15078982 
van Waardenburg RCAM, de Jong LA, van Eijndhoven MAJ, Verseyden C, Pluim D, Jansen LET, Bjornsti M-A, Schellens JHM. Platinated DNA adducts enhance poisoning of DNA topoisomerase I by camptothecin. J Biol Chem 279(52):54502-54509, 2004.  15471886 
Jacquiau HR#, van Waardenburg RCAM#, Reid RJD, Woo MH, Guo H, Johnson EJ, Bjornsti M-A. Defects in SUMO conjugation and deconjugation alter cell sensitivity to DNA topoisomerase I-induced DNA damage. J Biol Chem 280(25):23566-23575, 2005. #Contributed equally to this work.  15817450 
van Waardenburg RCAM, Duda D, Lancaster CS, Schulman BA, Bjornsti M-A. Distinct functional domains of Ubc9 dictate cell survival and resistance to genotoxic stress. Mol Cell Biol 26(13): 4958-4969, 2006  16782883 
Duda DM#, van Waardenburg RCAM#, Borg LA, McGarity S, Waddell MB, Bjornsti M-A, Schulman BA. Structure of a SUMO-binding-motif mimic bound to Smt3-Ubc9p: conservation of a noncovalent Ubquitin-like protein-E2 complex as a platform for selective interactions within a SUMO pathway. J Mol Biol 369: 619-630, 2007. #Contributed equally to this work.  17475278 
He X#, van Waardenburg RCAM#, Babaoglu K, Price AC, Nitiss KC, Nitiss JL, Bjornsti M-A, White SW. Mutation of a conserved active site residue converts Tyrosyl-DNA phophodiesterase I into a DNA topoisomerase-dependent poison. J Mol Biol 372:1070-1081, 2007. # Contributed equally to this work. F1000prime recomendation  17707402 
Gajewski A, Comeaux EQ, Jafari N, Bharatham N, Basford D, White SW, van Waardenburg RCAM. Analysis of the active-site mechanism of tyrosyl-DNA phosphodieasterase I: A member of the phospholipase D superfamily. J Mol Biol 415: 741-758, 2012.  22155078 
Feduska JM, Aller SG, Garcia PL, Cramer SL, Council LN, van Waardenburg RCAM, Yoon KJ. ICAM-2 confers a non-metastatic phenotype in neuroblastoma cells by interaction with α-actinin. Oncogene 34(12):1553-62, 2015   24704826 
Comeaux EQ and van Waardenburg RCAM. Tyrosyl-DNA Phosphodiesterase I Resolves both Natural and Chemically Induced DNA Adducts and its Potential as a Therapeutic Target. Drug Metabolism Reviews 46: 494-507, 2014.  25327705 
Comeaux EQ, Cuya SM, Kojima K, Jafari N, Wanzeck KC, Mobley JA, Bjornsti M-A, and van Waardenburg RCAM. Tyrosyl-DNA Phosphodiesterase I Catalytic Mutants Reveal an Alternative Nucleophile that can Catalyze Substrate Cleavage. J Biol. Chem. 290(10): 6203-14, 2015.   25609251 

Structure-function analysis, Mechanism of Action of proteins and drugs (chemotherapeutics), Drug Development for novel therapeutic targets, Post-translational modification by Ubiquitin and SUMO (Small Ubiqitin like modifier), Protein interactions