Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells

By Thomas M. Carlile, Maria F Rojas-Duran, Boris Zinshteyn, H. Shin, Kristen M. Bartoli, Wendy V. Gilbert. Nature, 2014

940 citations recorded by the source corpus.

Post-transcriptional modification of RNA nucleosides occurs in all living organisms. Pseudouridine, the most abundant modified nucleoside in non-coding RNAs, enhances the function of transfer RNA and ribosomal RNA by stabilizing the RNA structure. Messenger RNAs were not known to contain pseudouridine, but artificial pseudouridylation dramatically affects mRNA function—it changes the genetic code by facilitating non-canonical base pairing in the ribosome decoding centre. However, without evidence of naturally occurring mRNA pseudouridylation, its physiological relevance was unclear. Here we present a comprehensive analysis of pseudouridylation in Saccharomyces cerevisiae and human RNAs using Pseudo-seq, a genome-wide, single-nucleotide-resolution method for pseudouridine identification. Pseudo-seq accurately identifies known modification sites as well as many novel sites in non-coding RNAs, and reveals hundreds of pseudouridylated sites in mRNAs. Genetic analysis allowed us to assign most of the new modification sites to one of seven conserved pseudouridine synthases, Pus1–4, 6, 7 and 9. Notably, the majority of pseudouridines in mRNA are regulated in response to environmental signals, such as nutrient deprivation in yeast and serum starvation in human cells. These results suggest a mechanism for the rapid and regulated rewiring of the genetic code through inducible mRNA modifications. Our findings reveal unanticipated roles for pseudouridylation and provide a resource for identifying the targets of pseudouridine synthases implicated in human disease.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6060e4a1ebf20a67373de12494c21fc24c819b17

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Citations in the corpus

Accurate detection of m6A RNA modifications in native RNA sequences (2019, background): “Systematic efforts to characterize this regulatory layer have revealed that RNA modifications are far more widespread than previously thought, can be subjected to dynamic regulation, and can profoundly impact RNA processing stability and translation [5–10].”
RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation (2015, background): “In addition tom6A, recent studies have characterized the distribution of pseudouridine as another widespread and dynamic modification of mRNA (Carlile et al. 2014; Schwartz et al. 2014a).”
Rethinking m6A Readers, Writers, and Erasers (2017, methodology): “The m6A mapping concept was quickly applied to other modified nucleotides, resulting in transcriptome-wide maps of pseudouridine and other modified nucleotides (Carlile et al. 2014, Delatte et al. 2016, Lovejoy et al. 2014, Schwartz et al. 2014a).”
N6-methyladenosine Modulates Messenger RNA Translation Efficiency (2015, neutral): “, 2012), pseudouridine (Carlile et al., 2014; Schwartz et al., 2014), and N-methyladenosinde (Fu et al.”
Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use (2016, background): “Site-specific mRNA pseudouridylation occurs and is regulated by environmental conditions such as nutrient status (386) with AG decoding being distinctive (387).”