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Splicing Silencing by the CUGBP2 Splicing Factor: Mechanism of Action and Combinatorial Code for Splicing Silencing with Implications for Autoregulation

Dembowski, Jill A. (2010) Splicing Silencing by the CUGBP2 Splicing Factor: Mechanism of Action and Combinatorial Code for Splicing Silencing with Implications for Autoregulation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Alternative pre-mRNA splicing adjusts the transcriptional output of the genome by generating related mRNAs from a single primary transcript, thereby expanding protein diversity. A fundamental unanswered question is how splicing factors achieve specificity in the selection of target substrates despite the recognition of information-poor sequence motifs. The CUGBP2 splicing regulator plays a key role in the brain region-specific silencing of the NI exon of the NMDA R1 receptor. However, the sequence motifs utilized by this factor for specific target exon selection and the mechanism of splicing silencing are not understood. Here, I use chemical modification footprinting to map the contact sites of CUGBP2 to GU-rich motifs closely positioned at the boundaries of the branch sites of the NI exon, and demonstrate a mechanistic role for this specific arrangement of motifs for the regulation of branchpoint formation. General support for a branch site-perimeter-binding model is indicated by the identification of a group of novel target exons with a similar configuration of motifs that are silenced by CUGBP2. These results reveal an autoregulatory role for CUGBP2 as indicated by its direct interaction with functionally significant RNA motifs surrounding the branch sites upstream of exon 6 of the CUGBP2 transcript, itself. The perimeter-binding model explains how CUGBP2 can effectively embrace the branch site region to achieve the specificity needed for the selection of exon targets and the fine-tuning of alternative splicing patterns.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Dembowski, Jill A.jab67@pitt.eduJAB67
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGrabowski, Paulapag4@pitt.eduPAG4
Committee MemberLopez, A.
Committee MemberPeebles, Craigcpeebles@pitt.eduCPEEBLES
Committee MemberPipas, Jamespipas@pitt.eduPIPAS
Committee MemberBrodsky, Jeffreyjbrodsky@pitt.eduJBRODSKY
Date: 18 February 2010
Date Type: Completion
Defense Date: 17 September 2009
Approval Date: 18 February 2010
Submission Date: 23 September 2009
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Alternative Splicing; CUGBP2; NAPOR; pre-mRNA; NMDA Receptor; Splicing Regulation
Other ID:, etd-09232009-101602
Date Deposited: 10 Nov 2011 20:02
Last Modified: 15 Nov 2016 13:50


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