A major research focus is the regulatory mechanisms of aberrant RNA processing in cancer, particularly the regulation of alternative pre-mRNA splicing and processing, and miRNA biogenesis. One program studies the properties of Cyclin Dependent Kinase 12 (CDK12) in breast, ovarian, and prostate cancers. CDK12 interacts with spliceosomal proteins, RNA Pol2, and RNA processing factors to coordinately regulate transcription elongation and termination, poly-adenylation, and spliceosome activity. Using global quantitative mass spectrometry and RNA-seq methods in CRISPR/Cas9 engineered isogenic cancer cell line models the roles and mechanisms of CDK12 in regulating RNA processing are studied. Using small molecule inhibitors of CDK12 kinase activity the biological functions of CDK12 and its direct cellular targets are probed. A second program studies the oncogenic mechanisms of somatic mutations in the miRNA processing enzyme DICER1 in a broad spectrum of rare developmental cancers. The mutations affect only the RNase IIIb subdomain of DICER1 to abolish expression of 5P miRNAs. Isogenic cell lines and engineered mouse models are used to study mutant Dicer function.
Aberrant RNA processing in cancer
Canada’s Michael Smith Genome Sciences Centre respectfully acknowledges that we operate on the traditional, ancestral and unceded territories of the xʷməθkwəy̓əm (Musqueam), Səl̓ílwətaʔ/Selilwitulh (Tsleil-Waututh), and Skwxwú7mesh (Squamish) nations who have cared and nurtured this land for all time. We give thanks, as uninvited guests, to be able to live and work on these lands.
