Exploring how cells alter RNA metabolism in response to stress
Cellular stress responses aim to promote cell survival until the stress has passed. An actively growing cell allocates energetic reserves towards activities that promote growth. Alternatively, a terminally differentiated cell will direct resources that fulfill the aim of that cell. However, in both cases, when subjected to acute stresses, cells conserve and redirect these energetic reserves towards activities that promote survival. These stresses include oxidative stress, viral infection, thermal shock, exposure to heavy metals, among others. Careful calibration of the stress response is critical. An inefficient response will fail to promote survival, resulting in cell death. Failure to mount an efficient response is particularly detrimental to terminally differentiated cells, such as neurons. As a result, neurodegenerative diseases often exhibit defects in stress response. Alternatively, cancer cells routinely co-opt stress response pathways to promote their survival at the expense of surrounding cells. We use a combination of microscopic techniques, traditional biochemical approaches, and cutting edge high-throughput techniques to interrogate how cells alter gene expression with a focus on alterations in RNA metabolism.
The biogenesis of ribosomes is one of the most energy-intensive tasks a cell undertakes. Each human ribosome contains 80 ribosomal proteins and four long non-coding RNAs. Proper assembly requires hundreds of additional assembly factors (AFs), pre-rRNA processing enzymes and rRNA modification enzymes. The entire process is intricately coordinated to produce one of the most complex molecular machines in the cell. Further compounding this task is the fact that each time a cell divides, it duplicates its ribosome content. Some estimates suggest that a cell contains up to 10 million ribosomes. We are interested in the molecular mechanisms that allow for the rapid and precise assembly of ribosomes and how their biogenesis is altered during a stress response when there is a diminished need for new ribosomes. We are particularly interested in the alteration of rRNA processing and modification during stress and disease.
REGULATION OF TRANSLATION
mRNA translation is the process by which mRNAs are decoded by the ribosome and tRNAs to synthesize new proteins. In response to stress, cells strictly regulate this process. The translation of mRNAs that encode pro-growth and housekeeping proteins are de-prioritized. Concurrently, cells will promote the expression of pro-survival proteins and detoxifying enzymes. The selectivity of which mRNAs are translated and which are not is controlled at the level of translation initiation. The cell can regulate the binding of proteins necessary for the translation initiation complex to form or prevent recognition of the start codon. Some of these processes lead to the formation of stress granules, non-membranous phase-separated condensates of stalled pre-initiation complexes. Regardless of these global events, some mRNAs escape regulation. Our lab studies how cell stress results in translation inhibition, the downstream consequences of this inhibition and, the mechanisms by which some mRNAs can escape regulation.
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