제1저자 김원규(병리학교실, BK21)
교신저자 김호근(병리학교실, BK21)
Sci Rep. 2017 Nov 20ɕ(1):15833. doi: 10.1038/s41598-017-16177-9.
mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion.
Kim WK1, Yun S1, Kwon Y1, You KT2, Shin N3, Kim J4, Kim H5.
1Department of Pathology and Brain Korea 21 PLUS Projects for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.2Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.3Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA.4Department of Pharmacology and Brain Korea 21 PLUS Projects for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.5Department of Pathology and Brain Korea 21 PLUS Projects for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. firstname.lastname@example.org.
mRNAs containing premature termination codons (PTCs) are rapidly degraded through nonsense-mediated mRNA decay (NMD). However, some PTC-containing mRNAs evade NMD, and might generate mutant proteins responsible for various diseases, including cancers. Using PTC-containing human genomic β-globin constructs, we show that a fraction (~30%) of PTC-containing mRNAs expressed from NMD-competent PTC-containing constructs were as stable as their PTC-free counterparts in a steady state. These PTC-containing mRNAs were monosome-enriched and rarely contributed to expression of mutant proteins. Expression of trace amounts of mutant proteins from NMD-competent PTC-containing constructs was not affected by inhibition of eIF4E-dependent translation and such expression was dependent on a continuous influx of newly synthesized PTC-containing mRNAs, indicating that truncated mutant proteins originated primarily in the pioneer round of translation. The generation of mutant proteins was promoted by UPF1 depletion, which induced polysome association of PTC-containing mRNAs, increased eIF4E-bound PTC-containing mRNA levels, and subsequent eIF4E-dependent translation. Our findings suggest that PTC-containing mRNAs are potent and regulatable sources of mutant protein generation.