Spliceosomal introns are ubiquitous non-coding RNAs that are typically destined for rapid debranching and degradation. Here we describe 34 excised introns in Saccharomyces cerevisiae that-despite being rapidly degraded in log-phase growth-accumulate as linear RNAs under either saturated-growth conditions or other stresses that cause prolonged inhibition of TORC1, which is a key integrator of growth signalling. Introns that become stabilized remain associated with components of the spliceosome and differ from other spliceosomal introns in having a short distance between their lariat branch point and 3' splice site, which is necessary and sufficient for their stabilization. Deletion of these unusual introns is disadvantageous in saturated conditions and causes aberrantly high growth rates in yeast that are chronically challenged with the TORC1 inhibitor rapamycin. The reintroduction of native or engineered stable introns suppresses this aberrant rapamycin response. Thus, excised introns function within the TOR growth-signalling network of S. cerevisiae and, more generally, excised spliceosomal introns can have biological functions.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464110 | PMC |
http://dx.doi.org/10.1038/s41586-018-0828-1 | DOI Listing |
Highly recurrent somatic mutations in the gene encoding the core splicing factor SF3B1 are drivers of multiple cancer types. SF3B1 is a scaffold protein that orchestrates multivalent protein-protein interactions within the spliceosome that are essential for recognizing the branchsite (BS) and selecting the 3' splice site during the earliest stage of pre-mRNA splicing. In this review, we first describe the molecular mechanism by which multiple oncogenic SF3B1 mutations disrupt splicing.
View Article and Find Full Text PDFRNA
January 2025
University of Helsinki, Institute of Biotechnology
Minor spliceosome is responsible for recognizing and excising a specific subset of divergent introns during the pre-mRNA splicing process. Mutations in the unique snRNA and protein components of the minor spliceosome are increasingly being associated with a variety of germline and somatic human disorders, collectively termed as minor spliceosomopathies. Understanding the mechanistic basis of these diseases has been challenging due to limited functional information on many minor spliceosome components.
View Article and Find Full Text PDFNat Commun
January 2025
Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
The assembly of repressive heterochromatin in eukaryotic genomes is crucial for silencing lineage-inappropriate genes and repetitive DNA elements. Paradoxically, transcription of repetitive elements within constitutive heterochromatin domains is required for RNA-based mechanisms, such as the RNAi pathway, to target heterochromatin assembly proteins. However, the mechanism by which heterochromatic repeats are transcribed has been unclear.
View Article and Find Full Text PDFSci Rep
January 2025
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.
High mortality and low response rates in lung cancer patients call for novel therapeutic targets. Data mining of whole-genome genetic dependency screens suggest Cell Division Cycle 40 (CDC40) to be an essential protein for lung cancer cell survival. We characterized CDC40 knockdown effects in multiple lung cancer cell lines, revealing induced cell cycle defects that resulted in strong growth inhibition and activation of apoptosis.
View Article and Find Full Text PDFJ Biol Chem
December 2024
Department of Molecular Cell and Developmental Biology, University of California, Santa Cruz, California, USA; Center for Molecular Biology of RNA, University of California, Santa Cruz, California, USA. Electronic address:
The spliceosome protein, SF3B1 associates with U2 snRNP during early spliceosome assembly for pre-mRNA splicing. Frequent somatic mutations in SF3B1 observed in cancer necessitates characterization of its role in identifying the branchpoint adenosine of introns. Remarkably, SF3B1 is the target of three distinct natural product drugs, each identified by their potent anti-tumor properties.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!