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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-3390

Malanga, M; Czubaty, A; Girstun, A; Staron, K; Althaus, F R (2008). Poly(ADP-ribose) binds to the splicing factor ASF/SF2 and regulates its phosphorylation by DNA topoisomerase I. Journal of Biological Chemistry, 283(29):19991-19998.

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Abstract

Human DNA topoisomerase I plays a dual role in transcription, by controlling DNA supercoiling and by acting as a specific kinase for the SR-protein family of splicing factors. The two activities are mutually exclusive, but the identity of the molecular switch is unknown. Here we identify poly(ADP-ribose) as a physiological regulator of the two topoisomerase I functions. We found that, in the presence of both DNA and the alternative splicing factor/splicing factor 2 (ASF/SF2, a prototypical SR-protein), poly(ADP-ribose) affected topoisomerase I substrate selection and gradually shifted enzyme activity from protein phosphorylation to DNA cleavage. A likely mechanistic explanation was offered by the discovery that poly(ADP-ribose) forms a high affinity complex with ASF/SF2 thereby leaving topoisomerase I available for directing its action onto DNA. We identified two functionally important domains, RRM1 and RS, as specific poly(ADP-ribose) binding targets. Two independent lines of evidence emphasize the potential biological relevance of our findings: (i) in HeLa nuclear extracts, ASF/SF2, but not histone, phosphorylation was inhibited by poly(ADP-ribose); (ii) an in silico study based on gene expression profiling data revealed an increased incidence of alternative splicing within a subset of inflammatory response genes that are dysregulated in cells lacking a functional poly(ADP-ribose) polymerase-1. We propose that poly(ADP-ribose) targeting of topoisomerase I and ASF/SF2 functions may participate in the regulation of gene expression.

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25 citations in Web of Science®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Pharmacology and Toxicology
DDC:570 Life sciences; biology
Language:English
Date:2008
Deposited On:02 Sep 2008 12:55
Last Modified:20 Jul 2014 20:04
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Funders:Swiss National Science Foundation
Additional Information:This research was originally published in Malanga, M; Czubaty, A; Girstun, A; Staron, K; Althaus, F R (2008). Poly(ADP-ribose) binds to the splicing factor ASF/SF2 and regulates its phosphorylation by DNA topoisomerase I. Journal of Biological Chemistry, 283(29):19991-19998. © the American Society for Biochemistry and Molecular Biology.
Publisher DOI:10.1074/jbc.M709495200
PubMed ID:18495665

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