Tags

Type your tag names separated by a space and hit enter

A mechanism underlying position-specific regulation of alternative splicing.
Nucleic Acids Res. 2017 12 01; 45(21):12455-12468.NA

Abstract

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.

Authors+Show Affiliations

Centre for Developmental Neurobiology, King's College London, London SE1 1UL, UK. School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.Centre for Developmental Neurobiology, King's College London, London SE1 1UL, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30053257

Citation

Hamid, Fursham M., and Eugene V. Makeyev. "A Mechanism Underlying Position-specific Regulation of Alternative Splicing." Nucleic Acids Research, vol. 45, no. 21, 2017, pp. 12455-12468.
Hamid FM, Makeyev EV. A mechanism underlying position-specific regulation of alternative splicing. Nucleic Acids Res. 2017;45(21):12455-12468.
Hamid, F. M., & Makeyev, E. V. (2017). A mechanism underlying position-specific regulation of alternative splicing. Nucleic Acids Research, 45(21), 12455-12468. https://doi.org/10.1093/nar/gkx901
Hamid FM, Makeyev EV. A Mechanism Underlying Position-specific Regulation of Alternative Splicing. Nucleic Acids Res. 2017 12 1;45(21):12455-12468. PubMed PMID: 30053257.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A mechanism underlying position-specific regulation of alternative splicing. AU - Hamid,Fursham M, AU - Makeyev,Eugene V, PY - 2017/07/13/received PY - 2017/09/26/accepted PY - 2018/7/28/entrez PY - 2018/7/28/pubmed PY - 2019/6/15/medline SP - 12455 EP - 12468 JF - Nucleic acids research JO - Nucleic Acids Res. VL - 45 IS - 21 N2 - 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. SN - 1362-4962 UR - https://www.unboundmedicine.com/medline/citation/30053257/A_mechanism_underlying_position_specific_regulation_of_alternative_splicing_ L2 - https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx901 DB - PRIME DP - Unbound Medicine ER -