Research Areas of Interest
Dr. Wong investigates mechanisms responsible for the gross structural maintenance of the genome, the role of telomeres and telomerase in preventing chromosome erosion, and the cellular pathways that respond to DNA damage. Most cancers and premature aging syndromes share an observable loss of genome integrity. Her long-term goal is to discover genetic and pharmacological means to control cellular changes that affect stable genome maintenance.
1.Non-canonical activities of telomerase reverse transcriptase in cancers
New evidence suggests that high telomerase activity promotes survival of cancer cells in stressful conditions, such as treatment with chemotherapeutic agents. These growth advantages provided by telomerase expression are mediated through cellular functions not related to telomere repair. We intend to deduce the mechanisms of these telomerase activities in detail, and develop pharmacological strategies to inhibit them.
2. Characterization of alternate nucleic acid structure and functions
G-quadruplexes (G4) are guanine-rich nucleic-acid sequences capable of forming non-Watson-Crick four-strand structures. To understand the epigenetics of these unusual nucleic acid structures, we partnered with medicinal chemist David Monchaud’s laboratory at the University of Burgundy to develop new tools for the visualization and to map the genomic and transcriptomic binding landscapes of these novel agents. Our ongoing collaboration aims to advance the development of novel G4 ligands for therapeutic applications.
3. Inheritance and disease mechanisms of X-linked dyskeratosis congenita
X-linked dyskeratosis congenita (X-DC) is a bone-marrow-failure syndrome, caused by mutations in the DKC-1 gene, which encodes for the housekeeping enzyme dyskerin. Dyskerin is a pseudouridinylase enzyme that modifies RNAs. This is important for the structural and functional integrity of ribosomes, which are responsible for protein translation. Dyskerin is also a component of the telomerase reverse transcriptase, which repairs the ends of chromosomes.
There are more than forty dyskerin mutations currently known to associate with X-DC. In collaboration with the National Institutes of Health in the US, we have and will continue to create model cell lines from X-DC patients, to study the inheritance and disease mechanism of X-DC, as a paradigm for pre-mature aging diseases.
4. Genetic variations in telomere maintenance
Epidemiological data has recently linked common genetic changes of members in the telomerase holoenzyme to high incidences of different cancers. Our hypothesis is that telomerase function is altered both positively and negatively by these genetic changes, and differentiating these different scenarios is important for the understanding of the etiology of the cancer types. We propose to study the effects of these variations in human culture cell models.
Nguyen KTTT and Wong JMY. Telomerase Biogenesis and Activities from the Perspective of Its Direct Interacting Partners. Cancers 12(6), E1679 doi: 10.3390/cancers12061679. (2020)
Thompson CAH and Wong JMY. Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance. Top. Med. Chem. 20(6):498-507 doi: 10.2174/1568026620666200131125110. (2020)
Renard I, Grandmougin M, Roux A, Yang SY, Lejault P, Pirrotta M, Wong JMY and Monchaud D. Small-molecule affinity capture of DNA/RNA quadruplexes and their identification in vitro and in vivo through the G4RP protocol. Nucleic Acids Res., 47(11):5502-5510 doi: 10.1093/nar/gkz215. (2019).
Yang SY, Lejault P, Chevrier S, Boidot R, Robertson AG, Wong JMY* and Monchaud D*. Transcriptome-wide identification of transient RNA G-quadruplexes in human cells. Nat Comm, 9(1):4730. doi: 10.1038/s41467-018-07224-8 (2018). * co-senior authors
Thompson CAH, Gu A, Yang SY, Mathew V, Fleisig HB, Wong JMY. Transient Telomerase Inhibition with Imetelstat Impacts DNA Damage Signals and Cell-Cycle Kinetics. Mol Cancer Res, 16(8):1215-1225. doi: 10.1158/1541-7786. (2018).
Amor S, Yang SY, Wong JMY*, & Monchaud, D*. Cellular detection of G-quadruplexes by optical imaging methods. Curr Protocol Cell Biol, (76):4.33.1–4.33.19. doi:10.1002/cpcb.29 (2017). * co-senior authors
Xu JL, Gu AY, Thumati NR, Wong JMY. Quantification of Pseudouridine Levels in Cellular RNA Pools with a Modified HPLC-UV Assay. Genes (Basel). 8(9). pii: E219. doi: 10.3390/genes8090219. (2017)
Yang SY, Amor S, Laguerre A, Wong JMY* and Monchaud D*. Realtime and Quantitative fluorescent live cell imaging with quadruplex specific red edge probe (G4-REP). Biochim Biophys Acta (General Subjects) (1861):1312–1320 (2017) * co-senior authors
Xu JL#, Khincha PP#, Giri N, Alter BP, Savage SA*, Wong JMY*. Investigation of Chromosome X Inactivation and Clinical Phenotypes in Female Carriers of DKC1 Mutations. J. Hematol. (2016) doi: 10.1002/ajh.24545. [Epub ahead of print]. # co-first authors, * co-senior authors
Laguerre A, Wong JM, Monchaud D. Direct visualization of both DNA and RNA quadruplexes in human cells via an uncommon spectroscopic method. Sci. Rep (accepted, August 2016). * co-senior authors
Fleisig HB*, Hukezalie KR*, Thompson CAH, Au-Yeung T, Ludlow A, Zhao RC and Wong JMY. Telomerase reverse transcriptase expression protects transformed human cells against DNA-damaging agents, and increases tolerance to chromosomal instability. Oncogene 35:218-27 (2016). * equal contributions
Dr. Judy Wong obtained her PhD in Pharmacology at the University of Toronto. After her graduate training, she went on to complete a Post-Doctoral Fellowship in the Department of Molecular and Cell Biology at the University of California, Berkeley.
Dr. Wong is an Associate Professor in the Faculty of Pharmaceutical Sciences at the University of British Columbia (UBC).