I obtained my PhD in Daniel Durocher lab at the Lunenfeld Institute of Mount Sinai Hospital, and Department of Molecular Genetics at the University of Toronto. With Dan I learned about using molecular biology, genetics, and cell biology to understand genome stability, DNA repair, and telomere biology. Meanwhile I graduated from a two-year radiation medicine program (EIRR21, now STARS21) in the Department of Radiation Oncology at University of Toronto and held a Certificate in Project Management from University of Toronto. With a CIHR fellowship and later a Mitacs Elevate Fellowship I further conducted postdoctoral work in the labs of Sachdev Sidhu and Jason Moffat in the Donnelly Centre at the University of Toronto. I learned from Dev and Jason how to “modulate” cell signalling using protein engineering, synthetic biology, and systems biology approaches. Here in my own lab, I propose to combine the expertise I gained from my PhD and Postdoc studies to further understand and modulate DNA damage responses for novel cancer therapeutics.
BSc – School of Life Sciences, Beijing Normal University
PhD – Department of Molecular Genetics, University of Toronto
Postdoctoral Fellow - The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto
My research team creates synthetic probes modulating protein-protein interactions to: 1) accelerate understanding of biology, and 2) facilitate development of novel therapeutics. For example, we systematically generated inhibitors and activators for E3 ubiquitin ligases to discover new enzyme catalytic mechanism and new E3 substrates: Zhang et al. Molecular Cell 2016; Gabrielsen et al. Molecular Cell 2017 We also create molecular tools to increase CRISPR-Cas9 genome-editing efficiency: Canny et al. Nature Biotechnology 2018 Finally, we showed that structure-based protein engineering enables development of anti-viral reagents for Middle East respiratory syndrome (MERS) coronavirus: Zhang et al. PLoS Pathogens 2017
Currently, we are interested in the following research projects:
Development of synthetic peptides and proteins to delineate biochemical mechanisms of E3 ubiquitin ligases
Engineering post-translational modifications to probe and rewire DNA damage signaling for cancer therapeutics
Improvement of CRISPR-based gene editing through directed evolution
Veggiani G, Gerpe MCR, Sidhu SS, Zhang W. (2019) Emerging drug development technologies targeting ubiquitination for cancer therapeutics. Pharmacology & Therapeutics 119, 139-154.
Zhang W, Sidhu SS. (2018) Drug development: Allosteric inhibitors hit USP7 hard. Nature Chemical Biology14, 110-111.
Canny MD, Moatti N, Wan LC, Fradet-Turcotte A, Krasner D, Mateos-Gomez P, Zimmermann M, Orthwein A, Juang YC, Zhang W, Noordermeer SM, Seclen E, Wilson MD, Vorobyov A, Munro M, Ernst A, Ng TF, Cho T, Cannon P, Sidhu SS, Sicheri F, Durocher D. (2018) Inhibition of 53BP1 favors homology-dependent DNA repair and increases CRISPR-Cas9 genome-editing efficiency. Nature Biotechnology 36, 95–102.
Gabrielsen M, Buetow L, Nakasone MA, Ahmed SF, Sibbet GJ, Smith BO, Zhang W*, Sidhu SS*, Huang DT*. (2017) A general strategy for discovery of inhibitors and activators of RING and U-box E3 ligases with ubiquitin variants. Molecular Cell 68, 456-470. (*Co-corresponding authors)
Zhang W, Ben-David M, Sidhu SS. (2017) Engineering cell signaling modulators from native protein-protein interactions. Current Opinion in Structural Biology 45, 25-35.
Zhang W, Bailey-Elkin BA, Knaap RCM, Khare B, Dalebout TJ, Johnson G, van Kasteren PB, McLeish N, Gu J, He W, Kikkert M, Mark BL, Sidhu SS. (2017) Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants. PLoS Pathogens 13(5): e1006372. https://doi.org/10.1371/journal.ppat.1006372
Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS. (2016) System-wide modulation of HECT E3 ligases with selective ubiquitin variant probes. Molecular Cell 62, 121-36. ⌘ Highlighted in the issue with accompanied preview: Canadeo LA, Huibregtse JM. (2016) A billion ubiquitin variants to probe and modulate the UPS. Molecular Cell 62, 2-4.
Zhang W, Durocher D. (2010) De novo telomere formation is suppressed by the Mec1-dependent inhibition of Cdc13 accumulation at DNA breaks. Genes & Development 24, 502-15. ⌘ Highly recommended by Drs. Virginia Zakian (Princeton), David Shore (Geneva), and Katherine Friedman (Vanderbilt) on Faculty of 1000. ⌘ Featured as “Top 7 in Cancer Biology” in March 2011 by The Scientist magazine®