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Deadenylation kinetics of mixed poly(A) tails at single-nucleotide resolution

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Lee, Young-suk, Levdansky, Yevgen, Jung, Yoonseok, Kim, V. Narry, Valkov, Eugene·2024·Nature Structural & Molecular Biology
DOI 10.1038/s41594-023-01187-1PMC PMC11102861
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Abstract

Shortening of messenger RNA poly(A) tails, or deadenylation, is a rate-limiting step in mRNA decay and is highly regulated during gene expression. The incorporation of non-adenosines in poly(A) tails, or ‘mixed tailing’, has been observed in vertebrates and viruses. Here, to quantitate the effect of mixed tails, we mathematically modeled deadenylation reactions at single-nucleotide resolution using an in vitro deadenylation system reconstituted with the complete human CCR4–NOT complex. Applying this model, we assessed the disrupting impact of single guanosine, uridine or cytosine to be equivalent to approximately 6, 8 or 11 adenosines, respectively. CCR4–NOT stalls at the 0, −1 and −2 positions relative to the non-adenosine residue. CAF1 and CCR4 enzyme subunits commonly prefer adenosine but exhibit distinct sequence selectivities and stalling positions. Our study provides an analytical framework to monitor deadenylation and reveals the molecular basis of tail sequence-dependent regulation of mRNA stability.

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Metadata

Authors
Lee, Y.-S., Levdansky, Y., Jung, Y., Kim, V. N., & Valkov, E.
Affiliations
  • Korea Advanced Institute of Science and Technology (KR)
  • National Cancer Institute (US)
  • Institute for Basic Science (KR)
  • Seoul National University (KR)
  • Frederick National Laboratory for Cancer Research (US)
Corresponding author
  • Lee, Young-suk
  • Kim, V. Narry
  • Valkov, Eugene
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2024-02-19
Volume
31
Issue
5
Pages
826-834
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/s41594-023-01187-1
PMC
PMC11102861
OpenAlex
W4391927123
Cited by
21
References
3
Citations by year
2026: 9 · 2025: 11 · 2024: 1
FWCI
2.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KAIST Institutional Repository (KAIST) (submittedVersion)
Funders
  • National Research Foundation
  • Ministry of Science, ICT and Future Planning (IBS-R008-D1)
  • National Research Foundation of Korea (IBS-R008-D1, NRF-2021R1A4A3032789)
  • Institute for Basic Science (IBS-R008-D1, R008-D1)
  • Ministry of Science and ICT, South Korea (IBS-R008-D1)
  • National Institutes of Health
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
deadenylation, poly(A) tail, CCR4-NOT complex, CAF-1, CCR4, mRNA degradation, mRNA stability, sequence selectivity, mathematical modeling, single-nucleotide resolution
MeSH terms
Adenosine, Exoribonucleases, Humans, Kinetics, Poly A, RNA Nucleotidyltransferases, RNA, Messenger, RNA Stability, Receptors, CCR4

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