What we do at Judy Wong Lab.
Our laboratory studies the biology of chromosome structure and functions, with a particular focus on the mechanisms responsible for structural maintenance of the genome and regulation of genetic information flow. Our main research program investigates the roles of the chromosome end structures known as telomeres and their maintenance mechanisms, which include the telomerase-dependent and the homologous recombination-based alternative lengthening of telomere (ALT) pathways, in preventing chromosome erosion and in disease states. Another branch of our research addresses the functions and the genomic and transcriptomic locations of non-canonical chromatin structures, specifically the G-quadruplexes, and how chemical manipulation of their stability may affect the flow of genetic information. Our long-term goal is to discover genetic and pharmacological means of controlling genomic structures to induce cellular changes, in the treatment of different genetic diseases.
Our currently active projects are as follows below.
o1 Non-canonical activities of telomerase reverse transcriptase in cancer.
Telomerase is a specialized DNA polymerase that maintains the length of telomeres – nucleoprotein structures at chromosome ends – by synthesizing telomeric repeats de novo from an internal RNA template. Following telomerase deactivation which happens early on in development in most somatic cell types, telomeres shorten with each cell division, eventually reaching a length that would prompt either senescence or apoptosis. To overcome this natural, tumor-suppressing process of telomere attrition and gain immortality, up to 85% of human cancers upregulates telomerase reverse transcriptase (TERT), the catalytic component of telomerase, to keep their telomeres above the critical threshold. Importantly, our laboratory and others have found evidence of TERT having non-telomeric activities in the context of cancer, including a role in DNA damage response, given that its expression promotes cancer cells’ survival after treatment with DNA-damaging chemotherapeutic agents. However, the mechanism underlying this non-canonical TERT function remains poorly defined. We investigate the mechanism of TERT DNA damage response activities in detail, and develop pharmacological strategies to inhibit them.
o2 Role of chromatin remodeling proteins in Alternative Lengthening of Telomere (ALT) cancer.
ALT pathways are employed by around 10-15% of human cancers to maintain telomeres. ALT cancer engages a distinct homologous recombination-based telomere maintenance mechanism and is highly prevalent in several aggressive cancer types such as soft tissue sarcomas and neurological tumors. Telomeres of ALT cancers have been shown to maintain an open chromatin state compared to telomeres of telomerase-positive cancers, facilitating recombinational telomere synthesis. We aim to examine the role of selective chromatin remodeling factors in ALT to gain a better understanding of the ALT mechanism and identify potential therapeutic targets for these cancer types.
o3 Development of G-quadruplex Interacting Chemicals.
Guanine-rich regions of DNA and RNA can form transient four-stranded structures called G-quadruplexes (G4s), which act as roadblocks to nucleic acid metabolism processes including replication and transcription. G4-DNA formation generates double-stranded DNA breaks that can lead to genomic instability, while G4-RNA disrupts translation and splicing. Given their functional significance in genetic information flow, previous work from our group and others have investigated G4 stabilization as a novel therapeutic intervention against diseases with high metabolic demand, such as cancers. Although early-generation G4-stabilizing small molecules exhibit good cytotoxicity against various types of malignancy, their therapeutic window is too narrow for clinical application. Together with our long-term collaborator David Monchaud, we will continue our work on the development of novel G4-stabilizing ligands to circumvent these toxicity issues.
On the other hand, mutations that increase G4 abundance are implicated in neurodegenerative disorders ALS/FTD, as well as in genetic disorders that predispose mutant gene carriers to higher cancer risks; for instance, unresolved G4s are found to significantly contribute to the pathology of the Bloom and Werner premature aging syndromes. Theoretically, relieving G4 stress would be beneficial in these pathological settings; however, the development of G4-unwinding strategies has been lagging. We are developing first-generation G4-destabilizing small molecules as proof-of-principle to test the biological effects and toxicity of such therapeutic agents in healthy and disease models.
o4 Disease mechanisms and tumorigenesis in X-linked dyskeratosis congenita patients.
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome, with symptoms that include hematopoietic, epithelial and mucosal epithelial dysfunctions. DC was the first telomere biology disorder to be identified in humans. Accordingly, DC patients have defective telomere maintenance due to mutations in the various genes involved in the canonical telomere maintenance enzymatic complex, telomerase. DC patients have increased risk of developing cancers of hematopoietic and epithelial origin, a direct consequence of damaged telomeres not being repaired. Paradoxically, optimal telomere maintenance is crucial for malignant tumor growth, and how DC tumors overcome its telomerase deficiency limitation is not currently known. Understanding telomere length maintenance in DC tumors in contrast with tumors with adequate telomerase activity, and discovering DC tumors’ unique genetic vulnerabilities would provide new avenues for therapeutic interventions.
o5 Genetic variations in genome maintenance.
Epidemiological data links common genetic changes in the telomerase holoenzyme’s components 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 cancer types. We propose to study the effects of these variations in human cells and model the development of genome instability over time with culture cell models.