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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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Fig. 1 Mathematical modeling of deadenylation kinetics at single-nucleotide resolution. a, Schematic of a dynamic model of deadenylation. b, In vitro deadenylation assay with human CCR4–NOT complex. c, Heatmap presentation of the deadenylation assay data. Position 1 represents the A20 RNA substrate, and position 21 represents the tailless 7-mer RNA. Column-specific unity-based normalization was applied for data visualization. d, Parameter estimation and deadenylation kinetics at each single-nucleotide position from the 3′ end. Error bars represent the standard error of parameter estimation. e, In silico deadenylation based on the estimated parameters. Column-specific unity-based normalization was applied for data visualization.
Fig. 1 Mathematical modeling of deadenylation kinetics at single-nucleotide resolution. a, Schematic of a dynamic model of deadenylation. b, In vitro deadenylation assay with human CCR4–NOT complex. c, Heatmap presentation of the deadenylation assay data. Position 1 represents the A20 RNA substrate, and position 21 represents the tailless 7-mer RNA. Column-specific unity-based normalization was applied for data visualization. d, Parameter estimation and deadenylation kinetics at each single-nucleotide position from the 3′ end. Error bars represent the standard error of parameter estimation. e, In silico deadenylation based on the estimated parameters. Column-specific unity-based normalization was applied for data visualization.CC BY · PubMed Central
Fig. 2 Stalling effect of a single guanosine residue on human CCR4–NOT complex. a, Sequences of the synthetic 7-mer-A20 and 7-mer-A20G RNA substrates. Note the two guanosine residues at positions 7 and 14 for A20G. Position 21 represents the tailless 7-mer RNA. b, Schematic of the in vitro deadenylation analysis with human CCR4–NOT complex. c, In vitro deadenylation experiment with A20 and A20G RNA substrates (50 nM) and wild-type CCR4–NOT complex (25 nM). d, Left: heatmap analysis for A20 substrates. Column-specific unity-based normalization was applied for data visualization. Red arrowheads indicate the single-nucleotide positions 7, 14 and 21 from the 3′ end. Right: estimated deadenylation kinetics (nt min−1) based on the dynamic model. Error bars represent the standard error of parameter estimation. e, Deadenylation analysis as in d but with A20G RNA substrates. Error bars represent the standard error of parameter estimation. Heatmaps in d and e follow the same colour scale as in Fig. 1c,e. Source data
Fig. 2 Stalling effect of a single guanosine residue on human CCR4–NOT complex. a, Sequences of the synthetic 7-mer-A20 and 7-mer-A20G RNA substrates. Note the two guanosine residues at positions 7 and 14 for A20G. Position 21 represents the tailless 7-mer RNA. b, Schematic of the in vitro deadenylation analysis with human CCR4–NOT complex. c, In vitro deadenylation experiment with A20 and A20G RNA substrates (50 nM) and wild-type CCR4–NOT complex (25 nM). d, Left: heatmap analysis for A20 substrates. Column-specific unity-based normalization was applied for data visualization. Red arrowheads indicate the single-nucleotide positions 7, 14 and 21 from the 3′ end. Right: estimated deadenylation kinetics (nt min−1) based on the dynamic model. Error bars represent the standard error of parameter estimation. e, Deadenylation analysis as in d but with A20G RNA substrates. Error bars represent the standard error of parameter estimation. Heatmaps in d and e follow the same colour scale as in Fig. 1c,e. Source dataCC BY · PubMed Central
Fig. 3 Single pyrimidine residue produces a similar stalling effect but with greater impact at the terminal and antepenultimate positions. a, Sequences of the synthetic 7-mer-A20U and 7-mer-A20C RNA substrates (50 nM) and wild-type CCR4–NOT complex (25 nM). Note the two pyrimidine residues at position 7 and 14 for A20U and A20C. Position 21 represents the tailless 7-mer RNA. b, Left: heatmap analysis for A20U substrates. Column-specific unity-based normalization was applied for data visualization. Red arrowheads indicate the single-nucleotide positions 7, 14 and 21 from the 3′ end. Right: estimated deadenylation kinetics (nt min−1) based on the dynamic model. Error bars represent the standard error of parameter estimation. c, Deadenylation analysis as in b but with A20C RNA substrates. Error bars represent the standard error of parameter estimation. Heatmaps in b and c follow the same colour scale as in Fig. 1c,e.
Fig. 3 Single pyrimidine residue produces a similar stalling effect but with greater impact at the terminal and antepenultimate positions. a, Sequences of the synthetic 7-mer-A20U and 7-mer-A20C RNA substrates (50 nM) and wild-type CCR4–NOT complex (25 nM). Note the two pyrimidine residues at position 7 and 14 for A20U and A20C. Position 21 represents the tailless 7-mer RNA. b, Left: heatmap analysis for A20U substrates. Column-specific unity-based normalization was applied for data visualization. Red arrowheads indicate the single-nucleotide positions 7, 14 and 21 from the 3′ end. Right: estimated deadenylation kinetics (nt min−1) based on the dynamic model. Error bars represent the standard error of parameter estimation. c, Deadenylation analysis as in b but with A20C RNA substrates. Error bars represent the standard error of parameter estimation. Heatmaps in b and c follow the same colour scale as in Fig. 1c,e.CC BY · PubMed Central
Fig. 4 The distinct kinetic property of each catalytic subunit. a–d, CCR4E240A:CAF1 mutant deadenylation analysis with A20 (a), A20G (b), A20U (c) and A20C (d) RNA substrates. e–h, CCR4:CAF1D40A mutant deadenylation analysis with A20 (e), A20G (f), A20U (g) and A20C (h) RNA substrates. Left: heatmap analysis. Column-specific unity-based normalization was applied for data visualization. Incubation was done for up to 48 min as in Fig. 3. Right: estimated deadenylation kinetics (nt min−1) based on the dynamic model. Error bars represent the standard error of parameter estimation. Heatmaps in a–h follow the same colour scale as in Fig. 1c,e.
Fig. 4 The distinct kinetic property of each catalytic subunit. a–d, CCR4E240A:CAF1 mutant deadenylation analysis with A20 (a), A20G (b), A20U (c) and A20C (d) RNA substrates. e–h, CCR4:CAF1D40A mutant deadenylation analysis with A20 (e), A20G (f), A20U (g) and A20C (h) RNA substrates. Left: heatmap analysis. Column-specific unity-based normalization was applied for data visualization. Incubation was done for up to 48 min as in Fig. 3. Right: estimated deadenylation kinetics (nt min−1) based on the dynamic model. Error bars represent the standard error of parameter estimation. Heatmaps in a–h follow the same colour scale as in Fig. 1c,e.CC BY · PubMed Central
Fig. 5 Quantitative impact of mixed tails in terms of stalling deadenylation. a, The relative slowdown (or time for single-nucleotide removal) for each nucleotide variant and nucleotide position from the first non-A residue (that is, position 7). Unity-based normalization was applied for each type of human CCR4–NOT complex experiment. A, adenosine; G, guanosine; U, uridine; C, cytidine. b, The equivalent number of additional adenosines in terms of the deadenylation activity of CCR4E240A:CAF1 (n = 3) and CCR4:CAF1D40A (n = 2). The impact of the first residue (that is, position 7) was estimated. The barplot represents the mean number of additional adenosines, and error bars represent the s.e.m. c, A quantitative model of CCR4–NOT-dependent deadenylation. The solid lines represent strong deadenylation activity, and dashed lines represent relatively weak activity. d, The equivalent number of additional adenosines in terms of the deadenylation activity of wild-type complexes (n = 4). Impacts of both residues (positions 7 and 14) were estimated and are presented separately. The barplot represents the mean number of additional adenosines, and error bars represent the s.e.m. e, The quantitative impact of mixed tails in terms of the number of additional adenosines.
Fig. 5 Quantitative impact of mixed tails in terms of stalling deadenylation. a, The relative slowdown (or time for single-nucleotide removal) for each nucleotide variant and nucleotide position from the first non-A residue (that is, position 7). Unity-based normalization was applied for each type of human CCR4–NOT complex experiment. A, adenosine; G, guanosine; U, uridine; C, cytidine. b, The equivalent number of additional adenosines in terms of the deadenylation activity of CCR4E240A:CAF1 (n = 3) and CCR4:CAF1D40A (n = 2). The impact of the first residue (that is, position 7) was estimated. The barplot represents the mean number of additional adenosines, and error bars represent the s.e.m. c, A quantitative model of CCR4–NOT-dependent deadenylation. The solid lines represent strong deadenylation activity, and dashed lines represent relatively weak activity. d, The equivalent number of additional adenosines in terms of the deadenylation activity of wild-type complexes (n = 4). Impacts of both residues (positions 7 and 14) were estimated and are presented separately. The barplot represents the mean number of additional adenosines, and error bars represent the s.e.m. e, The quantitative impact of mixed tails in terms of the number of additional adenosines.CC BY · PubMed Central
Extended Data Fig. 1 Mathematical models of deadenylation. a. Schematic of a descriptive model of deadenylation. b. In silico deadenylation experiment and heatmap analysis comparing the descriptive and dynamic models. Column-specific unity-based normalization was applied for data visualization. A20 represents RNA with a poly(A) tail length 20, and A1 represents RNA with a single-adenosine tail.
Extended Data Fig. 1 Mathematical models of deadenylation. a. Schematic of a descriptive model of deadenylation. b. In silico deadenylation experiment and heatmap analysis comparing the descriptive and dynamic models. Column-specific unity-based normalization was applied for data visualization. A20 represents RNA with a poly(A) tail length 20, and A1 represents RNA with a single-adenosine tail.CC BY · PubMed Central
Extended Data Fig. 2 Alternative conditions for in vitro deadenylation experiments. a. Sequences of the synthetic 7-mer-A60 and 7-mer-A60G RNA substrates. b. Representative raw gel images from in vitro deadenylation experiment with A60 and A60G RNA substrates (50 nM) and wildtype CCR4-NOT complex (25 nM) of at least three technical and two biological replicates. c. Heatmap analysis for A60G substrates in (B). Column-specific unity-based normalization was applied for data visualization. Red arrowheads indicate the single-nucleotide positions 15, 30, and 45 from the 3′ end. d. Representative raw gel images after five-fold dilution from in vitro deadenylation experiment with A20 and A20G RNA substrates (250 nM) and wildtype CCR4-NOT complex (25 nM) of at least three technical and two biological replicates. e. Heatmap analysis for A20 and A20G substrates in (D). Column-specific unity-based normalization was applied for data visualization. Red arrowheads indicate the single-nucleotide positions 7, 14, and 21 from the 3′ end. f. Estimated deadenylation kinetics (nt / min) based on the dynamic model of (E). Error bars represent the standard error of parameter estimation. Source data
Extended Data Fig. 2 Alternative conditions for in vitro deadenylation experiments. a. Sequences of the synthetic 7-mer-A60 and 7-mer-A60G RNA substrates. b. Representative raw gel images from in vitro deadenylation experiment with A60 and A60G RNA substrates (50 nM) and wildtype CCR4-NOT complex (25 nM) of at least three technical and two biological replicates. c. Heatmap analysis for A60G substrates in (B). Column-specific unity-based normalization was applied for data visualization. Red arrowheads indicate the single-nucleotide positions 15, 30, and 45 from the 3′ end. d. Representative raw gel images after five-fold dilution from in vitro deadenylation experiment with A20 and A20G RNA substrates (250 nM) and wildtype CCR4-NOT complex (25 nM) of at least three technical and two biological replicates. e. Heatmap analysis for A20 and A20G substrates in (D). Column-specific unity-based normalization was applied for data visualization. Red arrowheads indicate the single-nucleotide positions 7, 14, and 21 from the 3′ end. f. Estimated deadenylation kinetics (nt / min) based on the dynamic model of (E). Error bars represent the standard error of parameter estimation. Source dataCC BY · PubMed Central
Extended Data Fig. 3 Supporting evidence related to Fig. 3. a. Representative raw gel images from in vitro deadenylation experiment with A20U and A20C RNA substrates (50 nM) and wildtype CCR4-NOT complex (25 nM) of at least three technical and two biological replicates. These images were used to quantitate deadenylation kinetics shown in Fig. 3. b. Re-analysis of TAIL-Seq data on HCMV-infected cells 10. The fraction of modified tails of HCMV RNA2.7 was calculated for RNAs with a poly(A) tail length of ≥25 nt (n = 1 TAIL-seq experiments). Source data
Extended Data Fig. 3 Supporting evidence related to Fig. 3. a. Representative raw gel images from in vitro deadenylation experiment with A20U and A20C RNA substrates (50 nM) and wildtype CCR4-NOT complex (25 nM) of at least three technical and two biological replicates. These images were used to quantitate deadenylation kinetics shown in Fig. 3. b. Re-analysis of TAIL-Seq data on HCMV-infected cells 10. The fraction of modified tails of HCMV RNA2.7 was calculated for RNAs with a poly(A) tail length of ≥25 nt (n = 1 TAIL-seq experiments). Source dataCC BY · PubMed Central
Extended Data Fig. 4 Supporting evidence related to Fig. 4. Representative raw gel images from in vitro deadenylation experiments with catalytic mutants (A,B) CCR4E240A:CAF1 and (C,D) CCR4:CAF1D40A of at least three technical and two biological replicates. These images were used to quantitate deadenylation kinetics shown in Fig. 4. Source data
Extended Data Fig. 4 Supporting evidence related to Fig. 4. Representative raw gel images from in vitro deadenylation experiments with catalytic mutants (A,B) CCR4E240A:CAF1 and (C,D) CCR4:CAF1D40A of at least three technical and two biological replicates. These images were used to quantitate deadenylation kinetics shown in Fig. 4. Source dataCC BY · PubMed Central

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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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