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Synthesis of Modified Thymidine and Intrastrand Cross-Linked DNA

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Synthesis of Modified Thymidine and Intrastrand Cross-Linked DNA Synthesis of Modified Thymidine and Intrastrand Cross-Linked DNA Probes to Investigate Repair by O6-Alkylguanine DNA Alkyltransferases and Bypass by Human DNA Polymerase η Derek Kyle O’Flaherty A Thesis in the Department of Chemistry and Biochemistry Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at Concordia University Montreal, Quebec, Canada January 2016 © Derek Kyle O’Flaherty, 2016 CONCORDIA UNIVERSITY School of Graduate Studies This is to certify that the thesis prepared By: Derek K. O'Flaherty Entitled: Synthesis of Modified Thymidine and Intrastrand Cross-Linked DNA Probes to Investigate Repair by O6-Alkylguanine DNA Alkyltransferases and Bypass by Human DNA Polymerase η and submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chemistry (Chemistry) complies with the regulations of the University and meets the accepted standards with respect to originality and quality. Signed by the final Examining Committee: ________________________________ Chair ________________________________ External Examiner Dr. Richard J. Wagner ________________________________ External to Program Dr. Laszlo Kalman ________________________________ Examiner Dr. Pat Forgione ________________________________ Examiner Dr. Sébastien Robidoux ________________________________ Thesis Supervisor Dr. Christopher J. Wilds Approved by: ___________________________________________ Dr. Peter Pawelek, Graduate Program Director Janurary 2016 _________________________________________ Dean of Faculty ii Abstract Synthesis of Modified Thymidine and Intrastrand Cross-Linked DNA Probes to Investigate Repair by O6-Alkylguanine DNA Alkyltransferases and Bypass by Human DNA Polymerase η Derek K. O’Flaherty, Ph.D. Concordia University, 2016 O6-Alkylguanine-DNA alkyltransferases (AGTs) are responsible for genomic maintenance by repairing O6-alkyl-2’-deoxyguanosine (O6-alkyl-dG) and O4-alkyl-thymidine (O4-alkyl-dT) adducts. AGT-mediated repair was investigated against DNA intrastrand cross-links (IaCL). A variety of cross-linked dimers linking the O6-atom of dG or O4-atom of dT were prepared synthetically to produce precursors for IaCL DNA that either lack or containing an intradimer phosphodiester group in the oligonucleotide backbone. Studies with AGTs demonstrated that: 1) O6-dG-alkylene-O6-dG flexible IaCL DNA (lacking the phosphodiester linkage) were efficiently repaired by hAGT. Repair of the model IaCL DNA occurred more efficiently in comparison to similar ICL DNA; 2) O6-dG-alkylene-O6-dG IaCL DNA containing the intradimer phosphodiester were moderately repaired by hAGT. Efficiency of the hAGT-mediated repair was contingent on the presence of the intradimer phosphate, which suggest conformational flexibility may be a requirement for repair by AGTs; 3) Flexible O4-dT-alkylene-O4-dT IaCL DNA evaded repair from all AGTs tested, whereas the flexible IaCL 5'-O4-dT-alkylene-O6-dG were efficiently repaired by hAGT. Interestingly, the 5'-O6-dG-alkylene-O4-dT was not proficiently repaired by hAGT supporting the importance of the 3'-phosphate group of the target dG nucleotide. 4) Flexible IaCL can be employed to generate DNA-protein cross-links (DPCs), with good conversions, as observed with repair of O6-dG-alkylene-O6-dG and 5'-O4-dT-alkylene-O6-dG by iii hAGT. The use of such cross-linking experiments may be useful for elucidating substrate discrimination across AGTs by X-ray crystallography. Translesion synthesis (TLS) may be activated by the cell as a coping mechanism when DNA damage evades repair or remains otherwise irreparable by repair mechanisms. Human DNA polymerase η (hPol η) is a key TLS Pol involved in the bypass of certain UV-induced DNA damage, and lesions formed by platinum-containing chemotherapeutics. Bypass experiments were conducted to determine if conformational freedom of the lesion impacted hPol η processivity. Towards this end, bicyclic pyrimidines linking the C5-atom to the O4-atom, by an ethylene or a propylene bridge, were synthesized as conformationally locked mimics of the biologically relevant DNA damage O4-methyl thymidine (O4-MedT) and O4-ethyl thymidine (O4-EtdT), respectively. Bypass studies revealed that: 1) The conformationally locked pyrimidyl analogues described above were bypassed by hPol η with different profiles, relative to O4-MedT and O4-EtdT. All thymidinyl modifications evoked an error-prone behavior from hPol η, with insertion of dGMP being incorporated most-frequently in the growing strand. 2) IaCL bypass profiles of O6-dG-alkylene-O6-dG containing the intradimer phosphodiester group behaved significantly different relative to those IaCL lacking it. hPol η inserted the correct nucleotide (dCMP) across the 3'-dG residue for all IaCL studied, whereas an error-prone behavior was observed across the 5'-dG residue. While the lack of the intradimer phosphodiester caused frameshift adduct formation across the 5'-dG, hPol η inserted the incorrect dTMP across the 5'- dG of the canonical IaCL DNA. More studies are required to elucidate whether this dependence is shared for other types of lesions. iv Acknowledgments For everyone that has helped me along the way, I thank you. I would like to begin by thanking my wife Meena Kathiresan for her undivided support. Meena, you have been an inspiration to me to become better on both a professional and personal level. It was with you that I found my true passion for science. I want to sincerely thank you for being in my life and having spent the better part of my graduate degree with me. You have motivated me in ways that words cannot describe. You also kicked me into gear for writing this document! I want to acknowledge my future children, whom I know will be an immense inspiration in my life. I cannot wait to meet you and start our very-own family. My deep appreciation go out to my mother Dominique Allaire and father Timothy O'Flaherty that have supported me throughout my entire studies, for as long as I can remember. You are the ones that made this all possible. I'll always cherish our movie nights and our family diners that brought so much joy and laughter to my life. I want to sincerely thank my brother Shawn O'Flaherty for his support and constant input. He has been an inspiration for me to strive for the best. I am immensely grateful to Dr. Christopher Wilds for his teachings and most-of-all his mentorship. I have interacted with Dr. Wilds since my first year of undergraduate studies at Concordia University as he was my supervisor for a Co-op work term during the summer of 2008. Dr. Wilds was the first person to teach me how to conduct organic chemistry in a research laboratory. Dr. Wilds’ had my best interest at heart and I have never been let down by him. Thinking of it at the moment, I cannot imagine how many reference letters Dr. Wilds had to write for me over the years; I count more than forty. He has guided me in so many ways and has been an excellent research supervisor. It has been an honor to work in Dr. Wilds' research group and I will never forget it. v My sincerest gratitude is extended to Dr. Martin Egli and Dr. F. Peter Guengerich for allowing me to conduct research in their laboratory at Vanderbilt University. Both visits were an eye-opening experience that I truly cherish. Thank you to Dr. Amritraj Patra, Dr. Pradeep Pallan, Dr. Yan Su, Dr. Qianqian Zhang, Dr. Ewa Kowal and Dr. Li Lei for all of your help during my stay. Many thanks to Ann Caldwell for lodging and helping me out on a daily basis. I would like to thank the current and past members of the lab, first and foremost Dr. Anne Noronha. Dr. Noronha was the first person I met from the lab, she actually introduced me to the lab premises in 2008. Thank you for having the patience to constantly answer my questions in the lab, to listen when I had a spontaneous idea for a project and to review my work and presentations. Thank you for taking the time to explain and teach me solid-phase synthesis. I know I'll always double (better still, triple) check all reagents bottle amounts, waste levels, argon pressure, amidite bottles, insoluble materials in the bottles, sequences, DNA cycle, coupling times, sequences, DNA cycle, sequences, DMT-off and CPG columns. Your meticulous approach to solid phase is what got me to where I am today. I want to extend many thanks to Dr. Francis McManus for teaching me the biochemistry, despite my chemistry background. Protein work initially intimidated me. I also really enjoyed our project brainstorming sessions, which really helped with the creativity aspect of my research. I would like to thank Dr. Gang Sun who shared a fumehood beside mine. You have always helped me out when I was dealing with chemistry issues. I would like to thank past lab members Jack Cheong and David de Bellefeuille for all the support during the early stages of my graduate studies. Special thanks go out to more recent lab colleagues William Copp, Lauralicia Sacre, Gianna Di Censo, and Chris Liczner for constant support and an enjoyable atmosphere in the lab. vi I want to extend appreciation for my committee members Dr. Sébastien Robidoux and Dr. Pat Forgione for their guidance. Further thanks to Dr. Robidoux for teaching me NMR. I would like to express gratitude to Dr. Joanne Turnbull for allocating space in her laboratory for radioactivity research and her helpful discussions. Thank you Dr. Alexey Denisov for helpful (NMR) discussions over the years. Thank you to Alain Tessier, Jean-Pierre Falgueyret, and Marcos Di Falco for MS analysis of small molecules and oligonucleotides. I would also like to extend thanks to members of other labs, past and present: Marc Ouellet, Andrew Barber, Dirk Ortgies, Mohammad Sharif, Stéphane Sévigny, Amanda Gabriel, Dylan McLaughlin and Harrison Saulnier. A quick shout-out to my little companions Ruby and Saffire.
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