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Cell Discov. 2015;1. pii: 15001. Epub 2015 May 5.

Premature Termination Codons Are Recognized in the Nucleus in A Reading-Frame Dependent Manner.

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State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
National Institute of Biological Sciences, Beijing 102206.
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.


mRNAs containing premature termination codons (PTCs) are known to be degraded via nonsense-mediated mRNA decay (NMD). Unexpectedly, we found that mRNAs containing any type of PTC (UAA, UAG, UGA) are detained in the nucleus whereas their wild-type counterparts are rapidly exported. This retention is strictly reading-frame dependent. Strikingly, our data indicate that translating ribosomes in the nucleus proofread the frame and detect the PTCs in the nucleus. Moreover, the shuttling NMD protein Upf1 specifically associates with PTC+ mRNA in the nucleus and is required for nuclear retention of PTC+ mRNA. Together, our data lead to a working model that PTCs are recognized in the nucleus by translating ribosomes, resulting in recruitment of Upf1, which in turn functions in nuclear retention of PTC+ mRNA. Nuclear PTC recognition adds a new layer of proofreading for mRNA and may be vital for ensuring the extraordinary fidelity required for protein production.


Nuclear retention; Premature termination codons (PTCs); Upf1; nuclear frame reading

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