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Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5' splice site selection.
Nucleic Acids Res. 2014 Oct 29; 42(19):12070-81.NA

Abstract

Alternative splicing (AS) modulates many physiological and pathological processes. For instance, AS of the BCL-X gene balances cell survival and apoptosis in development and cancer. Herein, we identified the polypyrimidine tract binding protein (PTBP1) as a direct regulator of BCL-X AS. Overexpression of PTBP1 promotes selection of the distal 5' splice site in BCL-X exon 2, generating the pro-apoptotic BCL-Xs splice variant. Conversely, depletion of PTBP1 enhanced splicing of the anti-apoptotic BCL-XL variant. In vivo cross-linking experiments and site-directed mutagenesis restricted the PTBP1 binding site to a polypyrimidine tract located between the two alternative 5' splice sites. Binding of PTBP1 to this site was required for its effect on splicing. Notably, a similar function of PTBP1 in the selection of alternative 5' splice sites was confirmed using the USP5 gene as additional model. Mechanistically, PTBP1 displaces SRSF1 binding from the proximal 5' splice site, thus repressing its selection. Our study provides a novel mechanism of alternative 5' splice site selection by PTBP1 and indicates that the presence of a PTBP1 binding site between two alternative 5' splice sites promotes selection of the distal one, while repressing the proximal site by competing for binding of a positive regulator.

Authors+Show Affiliations

Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy claudio.sette@uniroma2.it.

Pub Type(s)

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

Language

eng

PubMed ID

25294838

Citation

Bielli, Pamela, et al. "Regulation of BCL-X Splicing Reveals a Role for the Polypyrimidine Tract Binding Protein (PTBP1/hnRNP I) in Alternative 5' Splice Site Selection." Nucleic Acids Research, vol. 42, no. 19, 2014, pp. 12070-81.
Bielli P, Bordi M, Di Biasio V, et al. Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5' splice site selection. Nucleic Acids Res. 2014;42(19):12070-81.
Bielli, P., Bordi, M., Di Biasio, V., & Sette, C. (2014). Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5' splice site selection. Nucleic Acids Research, 42(19), 12070-81. https://doi.org/10.1093/nar/gku922
Bielli P, et al. Regulation of BCL-X Splicing Reveals a Role for the Polypyrimidine Tract Binding Protein (PTBP1/hnRNP I) in Alternative 5' Splice Site Selection. Nucleic Acids Res. 2014 Oct 29;42(19):12070-81. PubMed PMID: 25294838.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5' splice site selection. AU - Bielli,Pamela, AU - Bordi,Matteo, AU - Di Biasio,Valentina, AU - Sette,Claudio, Y1 - 2014/10/07/ PY - 2014/10/9/entrez PY - 2014/10/9/pubmed PY - 2015/3/11/medline SP - 12070 EP - 81 JF - Nucleic acids research JO - Nucleic Acids Res. VL - 42 IS - 19 N2 - Alternative splicing (AS) modulates many physiological and pathological processes. For instance, AS of the BCL-X gene balances cell survival and apoptosis in development and cancer. Herein, we identified the polypyrimidine tract binding protein (PTBP1) as a direct regulator of BCL-X AS. Overexpression of PTBP1 promotes selection of the distal 5' splice site in BCL-X exon 2, generating the pro-apoptotic BCL-Xs splice variant. Conversely, depletion of PTBP1 enhanced splicing of the anti-apoptotic BCL-XL variant. In vivo cross-linking experiments and site-directed mutagenesis restricted the PTBP1 binding site to a polypyrimidine tract located between the two alternative 5' splice sites. Binding of PTBP1 to this site was required for its effect on splicing. Notably, a similar function of PTBP1 in the selection of alternative 5' splice sites was confirmed using the USP5 gene as additional model. Mechanistically, PTBP1 displaces SRSF1 binding from the proximal 5' splice site, thus repressing its selection. Our study provides a novel mechanism of alternative 5' splice site selection by PTBP1 and indicates that the presence of a PTBP1 binding site between two alternative 5' splice sites promotes selection of the distal one, while repressing the proximal site by competing for binding of a positive regulator. SN - 1362-4962 UR - https://www.unboundmedicine.com/medline/citation/25294838/Regulation_of_BCL_X_splicing_reveals_a_role_for_the_polypyrimidine_tract_binding_protein__PTBP1/hnRNP_I__in_alternative_5'_splice_site_selection_ L2 - https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gku922 DB - PRIME DP - Unbound Medicine ER -