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The Modular Domain Structure of ASF/SF2: Significance for its Function as a Regulator of RNA Splicing
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

ASF/SF2 is an essential splicing factor, required for constitutive splicing, and functioning as a regulator of alternative splicing. ASF/SF2 is modular in structure and contains two amino-terminal RNA binding domains (RBD1 and RBD2), and a carboxy-terminal RS domain. The results from my studies show that the different activities of ASF/SF2 as a regulator of alternative 5’ and 3’ splice site selection can be attributed to distinct domains of ASF/SF2.

I show that ASF/SF2-RBD2 is both necessary and sufficient to reproduce the splicing repressor function of ASF/SF2. A SWQDLKD motif was shown to be essential for the splicing repressor activity of ASF/SF2. In conclusion, this study demonstrated that ASF/SF2 encodes for distinct domains responsible for its function as a splicing enhancer (the RS domain) or a splicing repressor (the RBD2) protein. Using a model transcript containing two competing 3’ splice sites it was further demonstrated that the activity of ASF/SF2 as a regulator of alternative 3’ splice site selection was directional: i.e. resulting in RS or RBD1 mediated activation of upstream 3’ splice site selection while simultaneously causing an RBD2 mediated repression of downstream 3’ splice site usage.

In alternative 5’ splice site selection, the RBD2 alone was sufficient to reproduce the activity of the full-length protein as an inducer of proximal 5’ splice site usage, while RBD1 had the opposite effect and induced distal 5’ splice site selection. The conserved SWQDLKD motif and the RNP-1 type RNA recognition motif in ASF/SF2-RBD2 were both essential for this induction. The activity of the ASF/SF2-RBD2 domain as a regulator of alternative 5’ splice site was shown to correlate with the RNA binding capacity of the domain.

Collectively, my results suggest that the RBD2 domain in ASF/SF2 plays the most decisive role in the alternative 5’ and 3’ splice site regulatory activities of ASF/SF2.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 51
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1287
Keywords [en]
Molecular biology, pre-mRNA splicing, alternative splicing, splicing regulation, SR proteins, ASF/SF2, modular domains, adenovirus, MLTU L1, E1A, MS2
Keywords [sv]
Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-3579ISBN: 91-554-5737-1 (print)OAI: oai:DiVA.org:uu-3579DiVA, id: diva2:163323
Public defence
2003-10-23, C8:305, BMC, Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-09-24 Created: 2003-09-24Bibliographically approved
List of papers
1. Human Splicing Factor ASF/SF2 Encodes for a Repressor Domain Required for Its Inhibitory Activity on Pre-mRNA Splicing
Open this publication in new window or tab >>Human Splicing Factor ASF/SF2 Encodes for a Repressor Domain Required for Its Inhibitory Activity on Pre-mRNA Splicing
2002 (English)In: The Journal of Biological Chemistry, ISSN 0021-9258, Vol. 277, no 15, p. 12579-12586Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90832 (URN)
Available from: 2003-09-24 Created: 2003-09-24 Last updated: 2011-06-30Bibliographically approved
2. Distinct functions of ASF/SF2 domains in the regulation of adenovirus L1 alternative 3' splice site selection
Open this publication in new window or tab >>Distinct functions of ASF/SF2 domains in the regulation of adenovirus L1 alternative 3' splice site selection
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-90833 (URN)
Available from: 2003-09-24 Created: 2003-09-24 Last updated: 2011-06-30Bibliographically approved
3. The RNA binding domains of human splicing factor ASF/SF2 determine alternative 5' splice site selection
Open this publication in new window or tab >>The RNA binding domains of human splicing factor ASF/SF2 determine alternative 5' splice site selection
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-90834 (URN)
Available from: 2003-09-24 Created: 2003-09-24 Last updated: 2011-06-30Bibliographically approved

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