Derek O’Flaherty

Assistant Professor

College of Computational, Mathematical and Physical Sciences, Department of Chemistry

Research Areas

Origins of Life
Organic Chemistry
Biochemistry
Biophysics

Education and Employment Background

Derek O’Flaherty is from Montreal (Canada), where he completed an Honours B.Sc. in Chemistry at Concordia University (Montreal, Canada) with a Minor in Multidisciplinary Sciences, and was a member of the Co-Operative Education program. He performed undergraduate research on the synthesis of cross-linked DNA oligonucleotides under the supervision of Professor Christopher Wilds. He then pursed a PhD in the Wilds lab at Concordia University, conducting research on the preparation of DNA containing, novel, site-specific chemical modifications as mimics of biologically relevant DNA damage. These adducts were then investigated as substrates for the direct repair pathway and the polymerase lesion bypass mechanism. After completing the PhD in 2016, Derek joined Jack Szostak’s research group at Massachusetts General Hospital – Harvard University as a FRQNT (and later CIHR) Postdoctoral Fellow. There he developed strategies to improve the non-enzymatic replication of genetic polymers as it pertains to the origins of life and the assembly of a synthetic cell. In 2019, Derek joined Alnylam Pharmaceuticals Inc. working in the high-throughput synthesis group as a Scientist. In 2020, he became an Assistant Professor at the University of Guelph in the Chemistry Department, where he is focusing on developing nucleic acid biotechnology and assembling a synthetic cell.

Research Themes

Our group works on research at the interface of chemistry and biology, with a focus on nucleic acid chemistry. Projects in the laboratory cover two broad areas of research; nucleic acid biotechnology and origins of life. Group members are exposed to an interdisciplinary portfolio of techniques in organic chemistry, chemical biology, biochemistry and biophysics.

Group Members

Jagandeep Saraya, PhD candidate

Scott Sammons, PhD candidate

Nicholas Horton, PhD candidate

Michael Capperauld, MSc candidate

Peter Kim, MSc candidate (co-supervised with Prof. Rui Huang)

Abby Sham, MSc candidate

Evan Zakaria, MSc candidate

Research Opportunities

Highly qualified candidates for summer research, honours thesis, graduate studies and postdoctoral research are welcome to send your resume to Professor O'Flaherty by email.

The Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry (GWC²) is a joint graduate program offered by the Departments of Chemistry at the University of Guelph and the University of Waterloo. To apply for the MSc/PhD program, please visit GWC².

There are a number of scholarships and awards available at the University of Guelph for Canadian and international graduate students and postdoctoral fellows. For details, please visit:

List of Awards/Scholarships for Graduate Students at the University of Guelph

List of Awards/Scholarships Specific to Graduate Students at the College of Engineering and Physical Science

Scholarships and Awards Administrative Guidelines.

We thank all applicants for your interests in advance; only candidates selected for interview will be contacted.

Funding

NSERC Discovery Grant (RGPIN 2020−05043), a NSERC Alliance Catalyst Grant (ALLRP 57555822), Canadian Foundation for Innovation - John R. Evans Leaders Fund (project 43757), and the HFSP Research Grant-Early Career (RGY0062/2022: https://doi.org/10.52044/HFSP.RGY00622022.pc.gr.153594).

Publications

^‡ indicates equal contribution; * indicates corresponding authors

6. Saraya J. S., O’Flaherty D. K.* “A facile and general tandem oligonucleotide synthesis methodology for DNA and RNA” ChemBioChem, 2024, accepted (Very Important Paper)

5. Ding D. , Fang Z., Kim S. C., O’Flaherty D. K., Jia X., Stone T. B., Zhou L.*, Szostak J. W.* “An Unusual Base Pair Between Two 2-Thiouridines and its Implication for Nonenzymatic RNA Copying” J. Am. Chem. Soc., 2024, accepted

4. Akabane-Nakata M.*, Erande N. D., Kumar P., Degaonkar R., Gilbert J. A., Qin J., Mendez M., Woods L. B., Jiang Y., Janas M. M., O’Flaherty D. K., Zlatev I., Schlegel M. K., Matsuda S., Egli M., Manoharan M.* “siRNAs containing 2′-fluorinated Northern-methanocarbacyclic (2′-F-NMC) nucleotides: in vitro and in vivo RNAi activity and inability of mitochondrial polymerases to incorporate 2′-F-NMC NTPs” Nucleic Acid Res. 2021, 49, 2435–2449.

3. Janicki M., Kufner C. L., Todd Z .R., Kim S. C., O’Flaherty D. K., Szostak J. W., Šponer J., Góra R. W., Sasselov D. S., Szabla R.* “Ribose Alters the Photochemical Properties of the Nucleobase in Thionated Nucleosides” J. Phys. Chem. Lett. 2021, 12, 6707–6713.

2. Rubio-Sánchez R., O’Flaherty D. K., Wang A., Coscia F., Petris G., Di Michele L., Cicuta P., Bonfio C.* “Thermally Driven Membrane Phase Transitions Enable Content Reshuffling in Primitive Cells” J. Am. Chem. Soc., 2021, 143, 16589–16598.

1. Kim S., O’Flaherty D. K., Zhou L., Giurgiu C., Szostak J. W.* “The Emergence of RNA from the Heterogeneous Productsof Prebiotic Nucleotide Synthesis”, J. Am. Chem. Soc., 2021, 143, 3267-3279.

Postdoc and Graduate studies

^‡ indicates equal contribution; * indicates corresponding authors

29. Zhou, L.^‡; O’Flaherty, D. K.^‡; Szostak, J. W.* “Assembly of a Ribozyme Ligase from Short Oligomers by Nonenzymatic Ligation”, J. Am. Chem. Soc., 2020, 142, 15961–15965.

28. Zhou, L.^‡; O’Flaherty, D. K.^‡; Szostak, J. W.* “Template‐directed copying of RNA by non-enzymatic ligation”, Angew. Chem. Int. Ed., 2020, 59, 15682 – 15687.

27. O’Flaherty D. K.^‡*; Zhou, L.^‡; Szostak, J. W.* “Nonenzymatic RNA-templated synthesis of N3′→P5′ phosphoramidate DNA”, Bio-protocol, 2020, 10, e3734.

26. Kim S. C.; Zhou L.; Zhang W.; O’Flaherty D. K.; Rondo-Brovettoc V.; Szostak J. W.* “A model for the emergence of RNA from a prebiotically plausible mixture of ribonucleotides, arabinonucleotides and 2′-deoxynucleotides”, J. Am. Chem. Soc., 2020, 142, 2317-2326.

25. O’Flaherty D. K.^‡; Zhou L.^‡; Szostak J. W.* “Nonenzymatic template-directed synthesis of mixed-sequence 3′-NP-DNA up to 25 nucleotides long inside model protocells”, J. Am. Chem. Soc., 2019, 141, 10481-10488.

24. Zhou L.; Kim S. C.; Ho K. H.; O’Flaherty D. K.; Giurgiu C.; Wright T. W.; Szostak J. W.* “Non-enzymatic primer extension with strand displacement”, eLife, 2019, 8, e51888.

23. Lelyveld V. S.; O’Flaherty D. K.; Zhou L.; Izgu E. C.; Szostak J. W.* “DNA polymerase activity on synthetic N3′–P5′ phosphoramidate DNA templates”, Nucleic Acid Res., 2019, 47, 8941-8949.

22. Wright T. W.^‡; Giurgiu C.^‡; Zhang W.; Radakovic A.; O’Flaherty D. K.; Zhou L.; Szostak J. W.* “Prebiotically plausible ‘patching’ of RNA backbone cleavage through a 3′-5′ pyrophosphate linkage”. J. Am. Chem. Soc., 2019, 141, 18104-18112.

21. O’Flaherty D. K.^‡; Kamat N. P.^‡*; Mirza F. N.; Li L.; Prywes N.; Szostak J. W.* “Copying of mixed-sequence RNA templates inside model protocells”, J. Am. Chem. Soc., 2018, 140, 5171-5178.

20. Copp W.; O’Flaherty D. K.; Wilds C. J.* “Covalent capture of OGT’s active site using engineered human-E.coli chimera and intrastrand DNA cross-links”, Org. Biomol. Chem., 2018, 16, 9053-9058.

19. Sacre L.; O’Flaherty D. K.; Archambault P.; Copp W.; Peslherbe G. H.; Muchall H. M.; Wilds C. J.*; “O4-alkylated-2- deoxyuridine repair by O6-alkylguanine DNA alkyltransferase is augmented by a C5-fluorine modification. Chembiochem, 2018, 19, 575 – 582.

18. Giurgiu C.; Wright T. H.; O’Flaherty D. K.; Szostak J. W.* “A fluorescent G-quadruplex sensor for chemical RNA copying”, Angew. Chem. Int. Ed., 2018 57, 9844-9848.

17. Kim S. C.; O’Flaherty D. K; Zhou L.; Lelyveld V. S.; Szostak J. W.* “Inosine, but none of the 8-oxo-purines, is a plausible component of a primordial version of RNA”, Proc. Natl. Acad. Sci. U.S.A., 2018, 115, 13318-13323.

16. O’Flaherty D. K.; Wilds C. J.* “AGT activity towards intrstrand crosslinked DNA is modulated by the alkylene linker”, ChemBioChem, 2017, 18, 2351-2357.

15. Denisov A. Y.^‡: McManus F. M.^‡; O’Flaherty D. K.; Noronha A. M.; Wilds C. J.* “Structural basis of interstrand cross-link repair by O6-alkylguanine DNA alkyltransferase”, Org. Biomol. Chem., 2017, 15, 8361-8370.

14. Giurgiu C.; Li L.; O’Flaherty D. K.; Tam C. P.; Szostak J. W.* “A mechanistic explanation for the regioselectivity of nonenzymatic RNA primer extension”, J. Am. Chem. Soc., 2017, 139, 16741-16747.

13. Schoonhoven N. M.^‡; O’Flaherty D. K.^‡; McManus F. P.^‡; Sacre L.; Noronha A. M.; Kornblatt M. J.*; Wilds C. J.* “Altering residue 134 confers an increased substrate range of alkylated nucleosides to the E. coli OGT protein” Molecules, 2017, 22, 1948.

12. O’Flaherty D. K.; Wilds C. J.* “Site-specific covalent capture of human O6-alkylguanine-DNAalkyltransferase using single-stranded intrastrand cross-linked DNA”. Org. Biomol. Chem., 2017, 15, 189-196.

11. Li L.; Prywes N.; Tam C. P; O’Flaherty D. K.; Lelyveld V. S.; Izgu E. C.; Pal A.; Szostak J. W.* “Enhanced nonenzymatic RNA copying with 2-aminoimidazole activated nucleotides”, J. Am. Chem. Soc., 2017, 139, 1810-1813.

10. Xu W.; Kool D.; O’Flaherty D. K.; Keating A. M.; Sacre L.; Egli M.; Noronha A. M.; Wilds C. J.; Zhao L.* “O6-2′-Deoxyguanosine-butylene-O6-2′-deoxyguanosine DNA interstrand cross-links are replication-blocking and mutagenic DNA lesions” Chem. Res. Toxicol. 2016, 29, 1872-1882.

9. O’Flaherty D. K.; Wilds C. J.* “Preparation of intrastrand {G}O6-alkylene-O6{G} cross-linked oligonucleotides”, Curr. Protoc. Nucleic Acid Chem., 2016, 66, 5.17.1-5.17.24

8. O’Flaherty D. K.; Wilds C. J.* “O6-Alkylguanine DNA alkyltransferase activity towards intrastrand crosslinked DNA is influenced by the internucleotide linkage”, Chem Asian J, 2016, 11, 576-583.

7. O’Flaherty D. K.; Patra A.; Su Y.; Guengerich F. P.; Egli M.*; Wilds C. J.* “Lesion orientation of O4-alkylthymidine influences replication by human DNA polymerase η“, Chemical Science, 2016, 7, 4896-4904.

6. O’Flaherty D. K.; Wilds C. J.* “Synthesis, characterization and repair of a flexible O6-2′-deoxyguanosinealkylene-O6-2′-deoxyguanosine intrastrand cross-link”, Chem. Eur. J., 2015, 21, 10522-10529.

5. O’Flaherty D. K.; Guengerich F. P.; Egli M.*; Wilds C. J.* “Backbone flexibility influences nucleotide incorporation by human translesion DNA polymerase eta opposite intrastrand cross-linked DNA”, Biochemistry, 2015, 54, 7449-7456.

4. O’Flaherty D. K.^‡; Denisov A. Y.^‡; Noronha A. M.; Wilds C. J.* “NMR structure of an ethylene interstrand crosslinked DNA which mimics the lesion formed by 1,3-bis(2-chloroethyl)-1-nitrosourea”, ChemMedChem, 2014, 9
2099-2103.

3. O’Flaherty D. K.; Guengerich F. P.* “Steady-state kinetic analysis of DNA polymerase single-nucleotide incorporation products”, Curr. Protoc. Nucleic Acid Chem., 2014, 59, 7.21.1-7.21.13.

2. O’Flaherty D. K.; McManus F. P.; Noronha A. M.; Wilds C. J.* “Synthesis of Building Blocks and Oligonucleotides Containing {T}O4-Alkylene-O4{T} Interstrand Cross-Links”, Curr. Protoc. Nucleic Acid Chem., 2013, 55, 5.13.1-5.13.19.

1. McManus F. P.; O’Flaherty D. K.; Noronha A. M.; Wilds C. J.* “O4-Alkyl-2′-deoxythymidine cross-linked DNA to probe recognition and repair by O6-alkylguanine DNA alkyltransferases” Org. Biomol. Chem., 2012, 10, 7078-7090.

Published abstracts

1. Schoonhoven N. M.; Murphy S. P.; O’Flaherty D. K.; Noronha A. M.; Kornblatt M. J.; Wilds C. J.* “Synthesis, Biophysical and Repair Studies of O6-2′-deoxyguanosine Adducts by Escherichia coli OGT”, Nucleic Acids Symposium Series, 2008, 52, 449-450