Widespread alterations in RNA processing (splicing, polyadenylation, decay, etc.) are common in dynamic cell states during development and malignancy. For example, many cancers harbor elevated levels of intron-retained mRNAs across their transcriptomes, suggesting these cancer cells harbor infidelity in RNA splicing, defective decay, or both.
While important mechanisms of RNA quality control and RNA decay have been discovered, the mechanisms that restore RNA processing homeostasis, and link sensing of broad aberrations in RNA processing with cell death and survival are poorly understood. Is there a coordinated cellular response to RNA processing stress that is analogous to the DDR? Does further dysfunction of RNA processing overwhelm a cancer’s ability to tolerate such stress, suggesting a therapeutic entry point? A major goal of our laboratory is to delineate:
• How common oncogenic drivers, such as the transcription factor c-MYC and spliceosome mutations, confer vulnerabilities across multiple levels of RNA processing.
• How mammalian cells respond to broad aberrations in RNA processing and explore how cancer cells differ in these responses.
