Splicing of pre-mRNA is an essential process for all eukaryotic dividing cells. Pre-mRNA splicing defects are implicated in numerous human diseases, including Alzheimer's disease and cancer, however, its cause is poorly understood. Using the nematode Caenorhabditis elegans as a model, we have recently shown that exposure to the environmental heavy metal cadmium can cause RNA splicing disruption, implicating loss of RNA metabolism regulation as a potential mechanism of cadmium toxicity. To understand the genetic mechanism of RNA splicing regulation under environmental stress, we sought to identify and characterize genes that, when knocked down, can protect against cadmium-induced RNA splicing errors. Using a C. elegans in vivo splicing reporter, we found that majority of the gene knock-downs that improved RNA splicing under stress encode various components of the protein synthesis machinery, including
ifg-1, which encodes the human eIF4G gene previously shown to regulate aging in worms. Knockdown of various protein translation related genes not only increase C. elegans lifespan but also enhance resistance to cadmium survival. Using RNA-seq, we found that
ifg-1 mutants show increases in expression of >80 genes that regulate RNA splicing, importantly,
ifg-1 mutants exposed to cadmium show a 50% decrease in cadmium-induced alternative splicing events observed in N2. Downstream of
ifg-1, we have identified RNA splicing regulators that do not affect N2 lifespan when knocked-down but abolishes
ifg-1's long-lived phenotype. Suppression of protein synthesis has been shown to be beneficial in promoting longevity and stress resistance in various organisms including C. elegans, and our study may have implicated a potential mechanism through which these physiological benefits are achieved in part by improvements to RNA splicing fidelity.