INTEGRATOR COMPLEX AS A STRESS SURVEILLANCE PROTEIN

Discovered in 2005, the evolutionarily conserved Integrator Complex was found to be the elusive protein machinery that catalyzes the 3’ end processing of snRNA transcripts involved in RNA splicing. Since then, studies have also shown that the Integrator regulates a wide-range of additional cellular functions including histone processing and transcriptional pause-release.

Recently, we discovered that the Integrator Complex malfunctions in C. elegans when exposed to the environmental contaminant cadmium, and that genetic disruption to the Integrator Complex mimics a state of cadmium stress. Deregulation to the Integrator Complex was recently linked to various human diseases and developmental disorders, and our identification of the Integrator complex being susceptible to environmental chemicals highlights the importance of understanding the regulatory mechanisms of this protein complex.

Currently, we are using genetic approaches to dissect the underlying regulatory network of the Integrator Complex during aging and while under stress. We hope to use this frame work to understand how this protein complex interacts with the environment to influence physiology.

Splicing of pre-mRNA is an essential process for dividing cells to regulate gene expression. Recent studies have shown that when RNA splicing is disrupted, it can lead to aging and numerous chronic diseases including cancer and neurological disorders.

In our laboratory, we are particularly interested in understanding how RNA splicing is affect when cells are exposed to toxic environmental stress. We recently discovered that chronic exposure to the carcinogenic heavy metal cadmium in C. elegans can disrupt RNA splicing fidelity, and lead to subsequent transcriptome deregulation.

Currently, we are interested in studying genetic pathways that regulate RNA splicing while under stress, as well as in identifying potential small molecule compounds that can protect against this disruption.