Abstract
The polyadenosine (poly(A)) tail found on the 3'-end of almost all eukaryotic mRNAs is important for mRNA stability and regulation of translation. mRNA 3'-end processing occurs co-transcriptionally and involves more than 20 proteins to specifically recognize the polyadenylation site, cleave the pre-mRNA, add a poly(A) tail, and trigger transcription termination. The polyadenylation site (PAS) defines the end of the 3'-untranslated region (3'-UTR) and, therefore, selection of the cleavage site is a critical event in regulating gene expression. Integrated structural biology approaches including biochemical reconstitution of multi-subunit complexes, cross-linking mass spectrometry, and structural analyses by X- ray crystallography and single-particle electron cryo-microscopy (cryoEM) have enabled recent progress in understanding the molecular mechanisms of the mRNA 3'-end processing machinery. Here, we describe new molecular insights into pre-mRNA recognition, cleavage and polyadenylation.
Highlights
Most eukaryotic pre-mRNAs are capped at their 50-end, spliced at intronic sites, and polyadenylated at their 30end before they are exported from the nucleus as mature mRNAs
The molecular mechanism of polyadenylation site (PAS) RNA recognition by the mammalian 30-end processing machinery was recently revealed by two independently determined cryoEM structures of the human CPSF160– WDR33–CPSF30–Fip1 complex bound to AAUAAAcontaining RNA
The intricate and specific network of molecular interactions established between CPSF30, WDR33 and all six nucleotide positions of the PAS provides a rationale for the widespread conservation of the AAUAAA motif revealed by transcriptome-wide mapping of mammalian mRNA polyadenylation sites [19,20,21]
Summary
Most eukaryotic pre-mRNAs are capped at their 50-end, spliced at intronic sites, and polyadenylated at their 30end before they are exported from the nucleus as mature mRNAs. The 30-end processing machinery co-transcriptionally monitors nascent transcripts for specific sequences (Figure 1) and, upon recognition of the polyadenylation site (PAS), cleaves the pre-mRNA and adds a poly(A) tail to the newly generated 30-end [1]. Polyadenylation signals and RNA recognition sites of the 30-end processing machinery in yeast and human pre-mRNAs. Protein complexes that are proposed to recognize specific cis-acting elements within the polyadenylation signal are listed below their consensus sequences.
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