Mechanism of Nonsense-Mediated mRNA Decay Stimulation by Splicing Factor SRSF1

被引：52

作者：

Aznarez, Isabel ^{[1
,2
]}

Nomakuchi, Tomoki T. ^{[1
,3
]}

Tetenbaum-Novatt, Jaclyn ^{[1
,4
]}

Rahman, Mohammad Alinoor ^{[1
]}

Fregoso, Oliver ^{[1
,5
]}

Rees, Holly ^{[1
,6
]}

Krainer, Adrian R. ^{[1
]}

机构：

[1] Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA

[2] Stoke Therapeut, Bedford, MA 01730 USA

[3] Stony Brook Sch Med, Stony Brook, NY 11794 USA

[4] Long Isl Univ, Arnold & Marie Schwartz Coll Pharm & Hlth Sci, Brooklyn, NY 11201 USA

[5] Univ Calif Los Angeles, Dept Microbiol Immunol Mol Genet, Los Angeles, CA 90095 USA

[6] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

来源：

CELL REPORTS | 2018年 / 23卷 / 07期

基金：

加拿大健康研究院;

关键词：

EXON-JUNCTION COMPLEX; SR PROTEINS; GENE-EXPRESSION; FACTORS UPF2; REVEALS; NMD; TRANSLATION; PHOSPHORYLATION; SURVEILLANCE; BINDING;

D O I：

10.1016/j.celrep.2018.04.039

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The splicing factor SRSF1 promotes nonsense-mediated mRNA decay (NMD), a quality control mechanism that degrades mRNAs with premature termination codons (PTCs). Here we show that transcript-bound SRSF1 increases the binding of NMD factor UPF1 to mRNAs while in, or associated with, the nucleus, bypassing UPF2 recruitment and promoting NMD. SRSF1 promotes NMD when positioned downstream of a PTC, which resembles the mode of action of exon junction complex (EJC) and NMD factors. Moreover, splicing and/or EJC deposition increase the effect of SRSF1 on NMD. Lastly, SRSF1 enhances NMD of PTC-containing endogenous transcripts that result from various events. Our findings reveal an alternative mechanism for UPF1 recruitment, uncovering an additional connection between splicing and NMD. SRSF1's role in the mRNA's journey from splicing to decay has broad implications for gene expression regulation and genetic diseases.

引用

页码：2186 / 2198

页数：13

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