Abstract
Nonsense-mediated messenger RNA decay (NMD) controls mRNA quality and degrades physiologic mRNAs to fine-tune gene expression in changing developmental or environmental milieus. NMD requires that its targets are removed from the translating pool of mRNAs. Since the decay steps of mammalian NMD remain unknown, we developed assays to isolate and sequence direct NMD decay intermediates transcriptome-wide based on their co-immunoprecipitation with phosphorylated UPF1, which is the active form of this essential NMD factor. We show that, unlike steady-state UPF1, phosphorylated UPF1 binds predominantly deadenylated mRNA decay intermediates and activates NMD cooperatively from 5′- and 3′-ends. We leverage method modifications to characterize the 3′-ends of NMD decay intermediates, show that they are ribosome-bound, and reveal that some are subject to the addition of non-templated nucleotide. Uridines are added by TUT4 and TUT7 terminal uridylyl transferases and removed by the Perlman syndrome-associated exonuclease DIS3L2. The addition of other non-templated nucleotides appears to inhibit decay.
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Data have been deposited in the Gene Expression Omnibus with accession code GSE111818. Source Data for Figs. 2c,d, 3a,b,d, and 4b are available online. Additional data are available upon reasonable request
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23 October 2018
In the version of this paper originally published, in the PDF references 48–55 appeared in the reference list for the Methods section although they should have been in the reference list for the main text. The error has been corrected in the PDF now available.
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Acknowledgements
We thank J. Pelletier for hippuristanol, S. Ohno and A. Yamashita for anti-p-UPF1(S1078, S1096), D. Ermolenko for Biocomp Gradient Fractionator usage, the University of Rochester Genomics Research Center for assistance in NGS library design, construction, and sequencing support, the University of Rochester Confocal Microscopy Core Facility for technical advice regarding confocal microscopy, and B. Lucas, M. Popp, and X. Rambout for comments on the manuscript. This work was supported by the National Institutes of Health (NIH) grant number R01 GM59614 to L.E.M. Salary support for T.K. was derived in part from a post-doctoral FRAXA Research Foundation Fellowship. The NIH through grant number S10 OD021489-01A1 supported purchase of the Typhoon FLA 9500 Phosphorimager.
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T.K. and L.E.M. conceived the project, developed the methods, and analyzed the data. T.K. and K.M. performed the experiments. J.R.M. and T.K. performed computational analyses. T.K. and L.E.M. wrote the manuscript with help writing up the computational analyses from J.R.M.
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Supplementary Figure 1 Transcriptome-wide NMD-Degradome Sequencing (NMD-DegSeq) maps decay intermediate (DI) 3′-ends, revealing the existence of not only homogeneous but also heterogeneous non-templated nucleotide additions.
a, Supplemental details of transcriptome-wide NMD-DegSeq library construction. b, Western blot prior to (−) or after immunoprecipitation using rIgG or anti(α)-p-UPF1. The leftmost five lanes represent threefold serial dilutions of lysate prior to immunoprecipitation. c, Control experiment showing that there was neither RNA degradation during p-UPF1 immunoprecipitation (IP) nor non-specific binding in the anti(α)-p-UPF1 immunoprecipitation using in vitro–synthesized and 32P-labeled mouse β-actin mRNA, which is not an NMD target and was added to lysates prior to p-UPF1 immunoprecipitation. d, Primer extension assay workflow. See the Methods for experimental procedures. e, Size distribution (blue histogram) and cumulative size distribution (red line) of p-UPF1-bound decay intermediates analyzed for NMD-DegSeq. f, Mean read density of exonic sequence reads ± 500 nucleotides (nt) relative to the transcription start site (TSS). Sequence reads from paired-end reads before (−) immunoprecipitation (dotted line) or after (solid line) p-UPF1 immunoprecipitation are shown. g, As in f, except for exonic sequence reads ± 500 nt relative to the translation start codon. h, As in Fig. 1h, but for DDIT4 mRNA, aligned to the coding strand of the DDIT4 gene. TSS, transcription start site; TES, transcription end site; Alt TES, alternative transcription end site. i, Scheme for streamlined NMD-DegSeq. See the Methods for details. j, Western blotting (WB) before (−) or after immunoprecipitation of lysates of HEK293T-cells, which were treated with okadaic acid prior to lysis, using anti(α) p-UPF1 or, as a negative control, rabbit (r)IgG. The five leftmost lanes represent threefold serial dilutions of lysate prior to immunoprecipitation. k, SYBR-Gold staining of the dRLUC-Gl PTC decay intermediate. l, Sequences of dRLUC-Gl PTC decay intermediates in streamlined NMD-DegSeq. The PTC (red) and exon 1–exon 2 junction are shown in the reference sequence (RefSeq). PCR primers (sense, blue arrows; antisense, green arrows) and non-templated nucleotide additions (pink) are provided in the decay intermediates, for which numbers to the left of blue arrows denote the percent (%) that each decay intermediate constitutes relative to all sequenced decay intermediates. m, As in k, but for GADD45A decay intermediates. n, As in l, but for GADD45A decay intermediates. Results are representative of two independently performed experiments.
Supplementary Figure 2 Defining degradative activities that generate NMD decay intermediates.
a, Western blotting of the samples analyzed in Fig. 2c,d. The five leftmost lanes represent threefold serial dilutions of lysate. Norm, normal; PTC, premature termination codon; Ctl, control. b, As in a, using multiple siRNAs where indicated. c, Western blotting (WB), SYBR-Gold-stained RT–PCR products of full-length (FL) dRLUC-Gl or MUP mRNA. d, As in c, but RT–PCR products of full-length GADD45A NMD target and β-actin mRNA. e, Sequences of dRLUC-Gl PTC decay intermediates (DIs) obtained in HEK293T cells transfected with the specified siRNAs. The PTC (red), exon 1–exon 2 junction, and putative G-quadruplex-forming sequences (underlined) are shown in the reference sequence (RefSeq). PCR primers (sense, blue arrows; antisense, green arrows) and non-templated nucleotide additions (pink) are provided in the decay intermediates, for which numbers in parentheses specify the number of clones sequenced and numbers to the left of the blue arrows denote the percent (%) that each decay intermediate constitutes relative to all sequenced decay intermediates. f, Essentially as in e but for endogenous GADD45A mRNA. Ter (red) specifies the normal termination codon. Short sequencing products (<10 nt) were excluded from the analysis. NMD-DegNAs results are representative of two independently performed experiments.
Supplementary Figure 3 NMD-target degradation involves terminal uridylyl transferases.
a, Western blotting of the HEK293T cell lysates analyzed in Fig. 3a–d. The four leftmost lanes represent threefold serial dilutions of lysate. Ctl, control. b, As in Fig. 3d, but for analyzing RNAs with 3′-terminal A after normalization to their level in total-cell RNAs. c, As in b, but for analyzing RNAs with 3′-terminal G. d, As in b, but for analyzing RNAs with 3′-terminal C. e, As in Fig. 3d, but analyzing RNAs ending with UUUU. *P < 0.05 and **P < 0.01 pertain to comparisons to Ctl siRNA or XRN1 siRNA samples (unpaired two-tailed t test); n = 3–4, showing means with s.d.
Supplementary Figure 4 p-UPF1 localizes diffusely throughout cytoplasm with ribosomal proteins and other NMD factors, and fails to co-immunoprecipitate with RPL5 when translation is inhibited.
a, Western blotting of lysates of HeLa cells (5 × 106/100-mm dish) transiently transfected with the specified siRNA. Ctl, control. b, Immunofluorescence microscopy of Ctl siRNA-treated HeLa cells (5 × 104/well of a 24-well plate) to localize anti(α)-UPF1, anti-p-UPF1(S1089) or anti-p-UPF1(S1116) reactivity, shown in green, relative to anti-α-tubulin reactivity, shown in red, and nuclei, stained blue using DAPI. Scale bar, 10 μm. c, As in b but using UPF1 siRNA-treated cells. d, Western blotting of nuclear and cytoplasmic fractions of HEK293T cells (8 × 107/150-mm dish). e, As in Fig. 4a, but using the specified antibody. f, Western blotting of lysates of HeLa cells (5 × 106/100-mm dish) that were or were not (−) exposed to 200 nM of okadaic acid for 3 h. g, Immunofluorescence microscopy of okadaic acid–treated HeLa cells (5 × 104/well using a 24-well plate) to localize anti(α)-UPF1, anti-p-UPF1(S1089) or anti-p-UPF1(S1116) reactivity, shown in green, relative to anti-Dcp1a reactivity, shown in red. Nuclei were stained blue using DAPI. Solid boxed regions are threefold magnifications of the dotted boxed regions. Scale bar, 10 μm. h, Western blotting of the samples assayed in Fig. 4b. Translation inhibition was evaluated by measuring the abundance of cell division cycle 6 (CDC6) protein, which has a half-life of 2–4 h (Genes Dev. 14, 2330–2343, 2000; Eur. J. Biochem. 269, 1040–1046, 2002). i, As in h, but immunoprecipitation used anti(α)-RPL5. j, Using fractions from polysome profile of HEK293T cell lysates shown (top), western blotting (WB) using the specified antibody and ethidium bromide staining (EB) to analyze 28S and 18S rRNAs.
Supplementary Figure 5 Sequences of NMD decay intermediates from NMD-DegRPL5 and NMD-DegRibo.
a, Sequences of the dRLUC-Gl PTC decay intermediates obtained in Fig. 5c. The PTC (red) and exon 1–exon 2 junction are shown in the reference sequence (RefSeq). PCR primers (sense, blue arrows; antisense, green arrows) and non-templated nucleotide additions (pink) are provided in the decay intermediates, for which numbers to the left of the blue arrows denote the percent (%) that each decay intermediate constitutes relative to all sequenced decay intermediates. b, As in a, but for the GADD45A decay intermediates obtained in Fig. 5d. Ter (red) specifies the normal termination codon. c, dRLUC-Gl PTC decay intermediates were obtained in Fig. 5f. RNA samples were generated using the scheme outlined for polysome fractionation shown in Fig. 5a. d, As in c, but for the GADD45A NMD target decay intermediates obtained in Fig. 5g.
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Supplementary Figures 1–5, Supplementary Tables 2 and 3, and Supplementary Notes 1–5
Supplementary Table 1
Differential expression of RNA fragments that derived from bona fide NMD targets
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Kurosaki, T., Miyoshi, K., Myers, J.R. et al. NMD-degradome sequencing reveals ribosome-bound intermediates with 3′-end non-templated nucleotides. Nat Struct Mol Biol 25, 940–950 (2018). https://doi.org/10.1038/s41594-018-0132-7
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DOI: https://doi.org/10.1038/s41594-018-0132-7
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