HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA

Mohammad Alinoor Rahman, Akio Masuda, Kenji Ohe, Mikako Ito, David O. Hutchinson, Akila Mayeda, Andrew G Engel, Kinji Ohno

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

CHRNA1 gene, encoding the muscle nicotinic acetylcholine receptor alpha subunit, harbors an inframe exon P3A. Inclusion of exon P3A disables assembly of the acetylcholine receptor subunits. A single nucleotide mutation in exon P3A identified in congenital myasthenic syndrome causes exclusive inclusion of exon P3A. The mutation gains a de novo binding affinity for a splicing enhancing RNA-binding protein, hnRNP LL, and displaces binding of a splicing suppressing RNA-binding protein, hnRNP L. The hnRNP L binds to another splicing repressor PTB through the proline-rich region and promotes PTB binding to the polypyrimidine tract upstream of exon P3A, whereas hnRNP LL lacking the proline-rich region cannot bind to PTB. Interaction of hnRNP L with PTB inhibits association of U2AF 65 and U1 snRNP with the upstream and downstream of P3A, respectively, which causes a defect in exon P3A definition. HnRNP L and hnRNP LL thus antagonistically modulate PTB-mediated splicing suppression of exon P3A.

Original languageEnglish (US)
Article number2931
JournalScientific Reports
Volume3
DOIs
StatePublished - 2013

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Heterogeneous-Nuclear Ribonucleoprotein L
RNA Precursors
Exons
Heterogeneous-Nuclear Ribonucleoproteins
RNA-Binding Proteins
Proline
Congenital Myasthenic Syndromes
U1 Small Nuclear Ribonucleoproteins
Mutation
Nicotinic Receptors
Cholinergic Receptors
Nucleotides

ASJC Scopus subject areas

  • General

Cite this

Rahman, M. A., Masuda, A., Ohe, K., Ito, M., Hutchinson, D. O., Mayeda, A., ... Ohno, K. (2013). HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. Scientific Reports, 3, [2931]. https://doi.org/10.1038/srep02931

HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. / Rahman, Mohammad Alinoor; Masuda, Akio; Ohe, Kenji; Ito, Mikako; Hutchinson, David O.; Mayeda, Akila; Engel, Andrew G; Ohno, Kinji.

In: Scientific Reports, Vol. 3, 2931, 2013.

Research output: Contribution to journalArticle

Rahman, Mohammad Alinoor ; Masuda, Akio ; Ohe, Kenji ; Ito, Mikako ; Hutchinson, David O. ; Mayeda, Akila ; Engel, Andrew G ; Ohno, Kinji. / HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. In: Scientific Reports. 2013 ; Vol. 3.
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abstract = "CHRNA1 gene, encoding the muscle nicotinic acetylcholine receptor alpha subunit, harbors an inframe exon P3A. Inclusion of exon P3A disables assembly of the acetylcholine receptor subunits. A single nucleotide mutation in exon P3A identified in congenital myasthenic syndrome causes exclusive inclusion of exon P3A. The mutation gains a de novo binding affinity for a splicing enhancing RNA-binding protein, hnRNP LL, and displaces binding of a splicing suppressing RNA-binding protein, hnRNP L. The hnRNP L binds to another splicing repressor PTB through the proline-rich region and promotes PTB binding to the polypyrimidine tract upstream of exon P3A, whereas hnRNP LL lacking the proline-rich region cannot bind to PTB. Interaction of hnRNP L with PTB inhibits association of U2AF 65 and U1 snRNP with the upstream and downstream of P3A, respectively, which causes a defect in exon P3A definition. HnRNP L and hnRNP LL thus antagonistically modulate PTB-mediated splicing suppression of exon P3A.",
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AU - Rahman, Mohammad Alinoor

AU - Masuda, Akio

AU - Ohe, Kenji

AU - Ito, Mikako

AU - Hutchinson, David O.

AU - Mayeda, Akila

AU - Engel, Andrew G

AU - Ohno, Kinji

PY - 2013

Y1 - 2013

N2 - CHRNA1 gene, encoding the muscle nicotinic acetylcholine receptor alpha subunit, harbors an inframe exon P3A. Inclusion of exon P3A disables assembly of the acetylcholine receptor subunits. A single nucleotide mutation in exon P3A identified in congenital myasthenic syndrome causes exclusive inclusion of exon P3A. The mutation gains a de novo binding affinity for a splicing enhancing RNA-binding protein, hnRNP LL, and displaces binding of a splicing suppressing RNA-binding protein, hnRNP L. The hnRNP L binds to another splicing repressor PTB through the proline-rich region and promotes PTB binding to the polypyrimidine tract upstream of exon P3A, whereas hnRNP LL lacking the proline-rich region cannot bind to PTB. Interaction of hnRNP L with PTB inhibits association of U2AF 65 and U1 snRNP with the upstream and downstream of P3A, respectively, which causes a defect in exon P3A definition. HnRNP L and hnRNP LL thus antagonistically modulate PTB-mediated splicing suppression of exon P3A.

AB - CHRNA1 gene, encoding the muscle nicotinic acetylcholine receptor alpha subunit, harbors an inframe exon P3A. Inclusion of exon P3A disables assembly of the acetylcholine receptor subunits. A single nucleotide mutation in exon P3A identified in congenital myasthenic syndrome causes exclusive inclusion of exon P3A. The mutation gains a de novo binding affinity for a splicing enhancing RNA-binding protein, hnRNP LL, and displaces binding of a splicing suppressing RNA-binding protein, hnRNP L. The hnRNP L binds to another splicing repressor PTB through the proline-rich region and promotes PTB binding to the polypyrimidine tract upstream of exon P3A, whereas hnRNP LL lacking the proline-rich region cannot bind to PTB. Interaction of hnRNP L with PTB inhibits association of U2AF 65 and U1 snRNP with the upstream and downstream of P3A, respectively, which causes a defect in exon P3A definition. HnRNP L and hnRNP LL thus antagonistically modulate PTB-mediated splicing suppression of exon P3A.

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