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Pairing to the microRNA 3′ region occurs through two alternative binding modes, with affinity shaped by nucleotide identity as well as pairing position
Open accessPreprint — published as 10.7554/elife.69803
Abstract
MicroRNAs (miRNAs), in association with Argonaute (AGO) proteins, direct repression by pairing to sites within mRNAs. Compared to pairing preferences of the miRNA seed region (nucleotides 2–8), preferences of the miRNA 3′ region are poorly understood, due to the sparsity of measured affinities for the many pairing possibilities. We used RNA bind-n-seq with purified AGO2–miRNA complexes to measure relative affinities of >1,000 3′-pairing architectures for each miRNA. In some cases, optimal 3′ pairing increased affinity by >500-fold. Some miRNAs had two high-affinity 3′-pairing modes—one of which included additional nucleotides bridging seed and 3′ pairing to enable high-affinity pairing to miRNA nucleotide 11. The affinity of binding and the position of optimal pairing both tracked with the occurrence of G or oligo(G/C) nucleotides within the miRNA. These and other results advance understanding of miRNA targeting, providing insight into how optimal 3′ pairing is determined for each miRNA. HIGHLIGHTS: RNA bind-n-seq reveals relative affinities of >1,000 3′-pairing architectures Two distinct 3′-binding modes can enhance affinity, by >500-fold in some instances G and oligo(G/C) residues help define the miRNA 3′ segment most critical for pairing Seed mismatch identity can influence the contribution of compensatory 3′ pairing
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Metadata
- Authors
- McGeary, S. E., Bisaria, N., & Bartel, D. P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bartel, David P.
- Venue
- eLife
- Publisher
- openRxiv
- Published
- 2021-04-14
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8940178
- OpenAlex
- W4212846081
- Cited by
- 69
- References
- 1
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 15 · 2023: 13 · 2022: 6 · 2021: 2
- FWCI
- 5.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM087237, GM123719, GM118135, F32GM123719, R35GM118135)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- microRNA, RNA binding affinity, miRNA seed region, miRNA targeting, nucleotide identity, mRNA repression
- MeSH terms
- Binding Sites, Nucleotides, RNA, Messenger, MicroRNAs, Argonaute Proteins
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