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Molecular and Cellular Biology, October 2009, p. 5620-5631, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.01678-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cooperative-Binding and Splicing-Repressive Properties of hnRNP A1{triangledown} ,{dagger}

Hazeem L. Okunola1,2 and Adrian R. Krainer1*

Cold Spring Harbor Laboratory, P.O. Box 100, Cold Spring Harbor, New York 11724,1 Physiology and Biophysics Program, The State University of New York at Stony Brook, Stony Brook, New York 117242

Received 29 October 2008/ Returned for modification 24 November 2008/ Accepted 30 July 2009

hnRNP A1 binds to RNA in a cooperative manner. Initial hnRNP A1 binding to an exonic splicing silencer at the 3' end of human immunodeficiency virus type 1 (HIV-1) tat exon 3, which is a high-affinity site, is followed by cooperative spreading in a 3'-to-5' direction. As hnRNP A1 propagates toward the 5' end of the exon, it antagonizes binding of a serine/arginine-rich (SR) protein to an exonic splicing enhancer, thereby inhibiting splicing at that exon's alternative 3' splice site. tat exon 3 and the preceding intron of HIV-1 pre-mRNA can fold into an elaborate RNA secondary structure in solution, which could potentially influence hnRNP A1 binding. We report here that hnRNP A1 binding and splicing repression can occur on an unstructured RNA. Moreover, hnRNP A1 can effectively unwind an RNA hairpin upon binding, displacing a bound protein. We further show that hnRNP A1 can also spread in a 5'-to-3' direction, although when initial binding takes place in the middle of an RNA, spreading preferentially proceeds in a 3'-to-5' direction. Finally, when two distant high-affinity sites are present on the same RNA, they facilitate cooperative spreading of hnRNP A1 between the two sites.

* Corresponding author. Mailing address: Cold Spring Harbor Laboratory, P.O. Box 100, Cold Spring Harbor, NY 11724. Phone: (516) 367-8417. Fax: (516) 367-8815. E-mail: krainer{at}cshl.edu

{triangledown} Published ahead of print on 10 August 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2009, p. 5620-5631, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.01678-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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