Premature Termination Codons Are Recognized in the Nucleus in A Reading-Frame Dependent Manner.
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.
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.
Min
M
Shi
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.
Heng
H
Zhang
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.
Lantian
L
Wang
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.
Changlan
C
Zhu
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.
Ke
K
Sheng
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.
Yanhua
Y
Du
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.
Ke
K
Wang
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Anusha
A
Dias
National Institute of Biological Sciences, Beijing 102206.
She
S
Chen
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
Malcolm
M
Whitman
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.
Enduo
E
Wang
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Robin
R
Reed
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.
Hong
H
Cheng
Nuclear retention; Premature termination codons (PTCs); Upf1; nuclear frame reading