Expanding the MicroRNA Targeting Code: Functional Sites with Centered Pairing

By Chanseok Shin, Jin-Wu Nam, Kyle Kai-How Farh, H. R. Chiang, Alena Shkumatava, David P. Bartel. Molecules and Cells, 2010

647 citations recorded by the source corpus.

SUMMARY Most metazoan microRNA target sites have perfect pairing to the seed region, located near the miRNA 5’ end. Although pairing to the 3’ region sometimes supplements seed matches or compensates for mismatches, pairing to the central region has been known to function only at rare sites that impart Agronaute-catalyzed mRNA cleavage. Here we present “centered sites,” a class of microRNA target sites that lacks both perfect seed pairing and 3’-compensatory pairing and instead has 11–12 contiguous Watson–Crick pairs to the center of the microRNA. Although centered sites can impart mRNA cleavage in vitro (in elevated Mg2+), in cells they repress protein output without consequential Agronaute-catalyzed cleavage. Our study also identified extensively paired sites that are cleavage substrates in cultured cells and human brain. This expanded repertoire of cleavage targets and the identification of the centered site type help explain why central regions of many microRNAs are evolutionarily conserved.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/47bfc17543ec650ad96362c697d8fff3ec173279

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Citations in the corpus

An overview of microRNAs (2015, neutral): “matched targets have been identified[71-74].”
microRNAs in action: biogenesis, function and regulation (2023, background): “Other examples of non-conventional miRNA targeting include extensively ‘centred’ base-pairing 58 , and certain variations of interrupted seeds 59,60 (Fig.”
Metazoan MicroRNAs (2018, background): “…and other mammals, however, miRNA-directed slicing has been reported for only 20 cellular transcripts (Yekta et al., 2004; Davis et al., 2005; Shin et al., 2010), one circular RNA (Hansen et al., 2011), and a few viral mRNAs (Sullivan et al., 2005; Barth et al., 2008), and examples of…”
Desperately seeking microRNA targets (2010, background): “Recent studies provide examples of MREs located outside of the 3′ UTR (especially in the coding sequence (CDS)) or that lack exact seed pairing, but compensate by downstream complementarit”
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The rise of regulatory RNA (2014, background): “…is more complex and multifaceted than expected, with (for example) demonstrations that miRNA isoforms are developmentally regulated 89 that the target ‘seed’ sequence is only one factor in target recognition 90,91 , and that miRNAs can also act to impose transcriptional silencing 92 (Figure 2).”
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Development of microRNA therapeutics is coming of age (2014, neutral): “Apart from canonical seed match sites, other types of miRNA-binding sites, such as centered sites, 3 0 supplementary sites and bulged sites have also been described (Bartel, 2009; Shin et al , 2010; Chi et al , 2012).”
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Current prospects for RNA interference-based therapies (2011, background): “Data from several laboratories showed that miRNAs repress the initiation of translation [15] [16] [17] , although more recent work indicates that miRNA-mRNA complexes can be transported to cytoplasmic processing bodies 18 , after which deadenylation and mRNA degradation occurs 14, 19, 20 .”
starBase: a database for exploring microRNA–mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data (2010, background): “Recent reports revealed that the Ago protein also plays a role in miRNA-derived cleavage (47) and in miRNA processing (50) in animals.”