A mechanism underlying position-specific regulation of alternative splicing

Many RNA-binding proteins including a master regulator of splicing in developing brain and muscle, polypyrimidine tract-binding protein 1 (PTBP1), can either activate or repress alternative exons depending on the pre-mRNA recruitment position. When bound upstream or within regulated exons PTBP1 tend...

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Main Authors: Hamid, Fursham M., Makeyev, Eugene V.
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2018
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Online Access:https://hdl.handle.net/10356/88632
http://hdl.handle.net/10220/44671
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-886322023-02-28T17:02:42Z A mechanism underlying position-specific regulation of alternative splicing Hamid, Fursham M. Makeyev, Eugene V. School of Biological Sciences Amino Acid Sequence Alternative RNA Splicing Many RNA-binding proteins including a master regulator of splicing in developing brain and muscle, polypyrimidine tract-binding protein 1 (PTBP1), can either activate or repress alternative exons depending on the pre-mRNA recruitment position. When bound upstream or within regulated exons PTBP1 tends to promote their skipping, whereas binding to downstream sites often stimulates inclusion. How this switch is orchestrated at the molecular level is poorly understood. Using bioinformatics and biochemical approaches we show that interaction of PTBP1 with downstream intronic sequences can activate natural cassette exons by promoting productive docking of the spliceosomal U1 snRNP to a suboptimal 5′ splice site. Strikingly, introducing upstream PTBP1 sites to this circuitry leads to a potent splicing repression accompanied by the assembly of an exonic ribonucleoprotein complex with a tightly bound U1 but not U2 snRNP. Our data suggest a molecular mechanism underlying the transition between a better-known repressive function of PTBP1 and its role as a bona fide splicing activator. More generally, we argue that the functional outcome of individual RNA contacts made by an RNA-binding protein is subject to extensive context-specific modulation. NMRC (Natl Medical Research Council, S’pore) Published version 2018-04-11T09:00:26Z 2019-12-06T17:07:42Z 2018-04-11T09:00:26Z 2019-12-06T17:07:42Z 2017 Journal Article Hamid, F. M., & Makeyev, E. V. (2017). A mechanism underlying position-specific regulation of alternative splicing. Nucleic Acids Research, 45(21), 12455-12468. 0305-1048 https://hdl.handle.net/10356/88632 http://hdl.handle.net/10220/44671 10.1093/nar/gkx901 en Nucleic Acids Research © 2017 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 14 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Amino Acid Sequence
Alternative RNA Splicing
spellingShingle Amino Acid Sequence
Alternative RNA Splicing
Hamid, Fursham M.
Makeyev, Eugene V.
A mechanism underlying position-specific regulation of alternative splicing
description Many RNA-binding proteins including a master regulator of splicing in developing brain and muscle, polypyrimidine tract-binding protein 1 (PTBP1), can either activate or repress alternative exons depending on the pre-mRNA recruitment position. When bound upstream or within regulated exons PTBP1 tends to promote their skipping, whereas binding to downstream sites often stimulates inclusion. How this switch is orchestrated at the molecular level is poorly understood. Using bioinformatics and biochemical approaches we show that interaction of PTBP1 with downstream intronic sequences can activate natural cassette exons by promoting productive docking of the spliceosomal U1 snRNP to a suboptimal 5′ splice site. Strikingly, introducing upstream PTBP1 sites to this circuitry leads to a potent splicing repression accompanied by the assembly of an exonic ribonucleoprotein complex with a tightly bound U1 but not U2 snRNP. Our data suggest a molecular mechanism underlying the transition between a better-known repressive function of PTBP1 and its role as a bona fide splicing activator. More generally, we argue that the functional outcome of individual RNA contacts made by an RNA-binding protein is subject to extensive context-specific modulation.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Hamid, Fursham M.
Makeyev, Eugene V.
format Article
author Hamid, Fursham M.
Makeyev, Eugene V.
author_sort Hamid, Fursham M.
title A mechanism underlying position-specific regulation of alternative splicing
title_short A mechanism underlying position-specific regulation of alternative splicing
title_full A mechanism underlying position-specific regulation of alternative splicing
title_fullStr A mechanism underlying position-specific regulation of alternative splicing
title_full_unstemmed A mechanism underlying position-specific regulation of alternative splicing
title_sort mechanism underlying position-specific regulation of alternative splicing
publishDate 2018
url https://hdl.handle.net/10356/88632
http://hdl.handle.net/10220/44671
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