Journal
GENETICS
Volume 221, Issue 3, Pages -Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1093/genetics/iyac075
Keywords
RNA splicing; aging; environmental stress
Categories
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC) [04486]
- Saskatchewan Health Research Foundation (SHRF) Establishment Grant [4971]
- Western College of Veterinary Medicine (WCVM)
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This study reveals that protein translation suppression inhibits cadmium-induced alternative splicing. The ifg-1 mutant up-regulates RNA splicing regulatory genes controlled by the TGF-beta transcription factor SMA-2, and RNA splicing plays an essential role in promoting longevity and stress resistance.
Splicing of precursor mRNA is an essential process for dividing cells, and splicing defects have been linked to aging and various chronic diseases. Environmental stress has recently been shown to modify alternative splicing, and molecular mechanisms that influence stress-induced alternative splicing remain unclear. Using an in vivo RNA splicing reporter, we performed a genome-wide RNAi screen in Caenorhabditis elegans and found that protein translation suppression via silencing of the conserved eukaryotic initiation factor 4G (IFG-1/eIF4G) inhibits cadmium-induced alternative splicing. Transcriptome analysis of an ifg-1-deficient mutant revealed an overall decrease in intronic and intergenic reads and prevented cadmium-induced alternative splicing compared to the wild type. We found that the ifg-1 mutant up-regulates >80 RNA splicing regulatory genes controlled by the TGF-beta transcription factor SMA-2. The extended lifespan of the ifg-1 mutant is partially reduced upon sma-2 depletion and completely nullified when core spliceosome genes including snr-1, snr-2, and uaf-2 are knocked down. Depletion of snr-1 and snr-2 also diminished the enhanced cadmium resistance of the ifg-1 mutant. Together, these data describe a molecular mechanism through which translation suppression inhibits stress-induced alternative splicing and demonstrate an essential role for RNA splicing in promoting longevity and stress resistance in a translation-compromised mutant.
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