Abstract
RNA splicing entails the coordinated interaction of more than 150 proteins in the spliceosome, one of the most complex of the cell's molecular machines. We previously discovered that the RNA-binding motif protein 17 (RBM17), a component of the spliceosome, is essential for survival and cell maintenance. Here, we find that it interacts with the spliceosomal factors U2SURP and CHERP and that they reciprocally regulate each other's stability, both in mouse and in human cells. Individual knockdown of each of the three proteins induces overlapping changes in splicing and gene expression of transcripts enriched for RNA-processing factors. Our results elucidate the function of RBM17, U2SURP, and CHERP and link the activity of the spliceosome to the regulation of downstream RNA-binding proteins. These data support the hypothesis that, beyond driving constitutive splicing, spliceosomal factors can regulate alternative splicing of specific targets. De Maio et al. find that the splicing factor RBM17 establishes a physical and functional relation with U2SURP and CHERP. Knockdown of these U2 snRNP-associated spliceosomal components reveals their synergistic activity toward regulation of a given set of transcripts rather than a more predictable transcriptome-wide inhibition of splicing.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 726-736.e7 |
| Journal | Cell reports |
| Volume | 25 |
| Issue number | 3 |
| DOIs | |
| State | Published - Oct 16 2018 |
Bibliographical note
Funding Information:We thank the members of the Zoghbi and Liu laboratories for helpful suggestions and discussions and C.E. Alcott, Q. Tan, T.A. Cooper, and V.L. Brandt for valuable advice on the manuscript. V.A.G. is supported by the National Ataxia Foundation (Young Investigator Research Grant 2017), United States. J.Q. and S.Y.J. are supported by the NIH (P30CA125123, NCI center grant), United States. This project was supported by the Howard Hughes Medical Institute, United States; the NIH/National Institute of Neurological Disorders and Stroke (NIH/NINDS) (2R37NS027699), United States; the Baylor College of Medicine IDDRC (U54HD083092, administrative core), United States; the Cancer Prevention Research Institute of Texas (RP170387), Houston endowment, Huffington foundation (Z.L.), United States; the NIH/National Institute of Aging (NIH/NIA) (AG05733902), United States; the NIH/National Institute of General Medical Sciences (NIH/NIGMS) (GM12003302), United States; a P30 Digestive Disease Center support grant (NIDDK-DK56338, genomic and RNA profiling core), United States; and a P30 Cancer Center support grant (NCI-CA125123) at Baylor College of Medicine, United States.
Funding Information:
We thank the members of the Zoghbi and Liu laboratories for helpful suggestions and discussions and C.E. Alcott, Q. Tan, T.A. Cooper, and V.L. Brandt for valuable advice on the manuscript. V.A.G. is supported by the National Ataxia Foundation (Young Investigator Research Grant 2017), United States. J.Q. and S.Y.J. are supported by the NIH ( P30CA125123 , NCI center grant), United States. This project was supported by the Howard Hughes Medical Institute, United States ; the NIH/National Institute of Neurological Disorders and Stroke (NIH/NINDS) ( 2R37NS027699 ), United States; the Baylor College of Medicine IDDRC ( U54HD083092 , administrative core), United States; the Cancer Prevention Research Institute of Texas ( RP170387 ), Houston endowment, Huffington foundation (Z.L.), United States; the NIH/National Institute of Aging (NIH/NIA) ( AG05733902 ), United States; the NIH/National Institute of General Medical Sciences (NIH/NIGMS) ( GM12003302 ), United States; a P30 Digestive Disease Center support grant ( NIDDK-DK56338 , genomic and RNA profiling core), United States; and a P30 Cancer Center support grant ( NCI-CA125123 ) at Baylor College of Medicine, United States.
Publisher Copyright:
© 2018 The Authors
Keywords
- CHERP
- RBM17
- RNA homeostasis
- U2SURP
- cryptic splicing
- spliceosome
- splicing
