Abstract
Apolipoprotein B–editing enzyme, catalytic polypeptide-1 (APOBEC1) is a cytidine deaminase initially identified by its activity in converting a specific cytidine (C) to uridine (U) in apolipoprotein B (apoB) mRNA transcripts in the small intestine. Editing results in the translation of a truncated apoB isoform with distinct functions in lipid transport. To address the possibility that APOBEC1 edits additional mRNAs, we developed a transcriptome-wide comparative RNA sequencing (RNA-Seq) screen. We identified and validated 32 previously undescribed mRNA targets of APOBEC1 editing, all of which are located in AU-rich segments of transcript 3′ untranslated regions (3′ UTRs). Further analysis established several characteristic sequence features of editing targets, which were predictive for the identification of additional APOBEC1 substrates. The transcriptomics approach to RNA editing presented here dramatically expands the list of APOBEC1 mRNA editing targets and reveals a novel cellular mechanism for the modification of transcript 3′ UTRs.
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14 December 2011
In the version of this article initially published, financial support from the Starr Foundation was not acknowledged. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank C. Rice, H. Smith, D. Licatalosi and E. Fritz for critical reading of this manuscript; R. Darnell for discussion and suggestions; and G. Livshits for immunofluorescence assistance. This was supported by the Cancer Research Institute (training grants to B.R.R. and C.E.H.), by the National Institutes of Health (Medical Scientist Training Program grant GM07739 to B.R.R. and C.E.H.) and by a pilot grant through the Rockefeller Clinical and Translational Science Award program (National Institutes of Health National Center for Research Resources grant UL1RR024143 to F.N.P.). This work was supported by the Starr Foundation.
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B.R.R. and F.N.P. conceived of and designed the work presented; B.R.R. is responsible for data presented in Figures 1, 2, 3, 4 and 5; C.E.H. contributed data to Figure 5 and the Supplementary Figures M.M.M. is responsible for the statistical analysis underlying Figure 3 and Supplementary Figure 5; S.D. provided bioinformatics training and support; and B.R.R. and F.N.P. wrote the manuscript with considerable input from M.M.M., C.E.H. and S.D.
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Supplementary Figures 1–5, Supplementary Tables 1–3, 5 and 6 and Supplementary Methods (PDF 8464 kb)
Supplementary Table 4
APOBEC1 Sequence Pattern in RefSeq Transcripts. (XLS 84 kb)
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Rosenberg, B., Hamilton, C., Mwangi, M. et al. Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3′ UTRs. Nat Struct Mol Biol 18, 230–236 (2011). https://doi.org/10.1038/nsmb.1975
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DOI: https://doi.org/10.1038/nsmb.1975
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