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Cancer-associated missplicing of exon 4 influences the subnuclear distribution of the DNA replication factor CIZ1

Rahman, F.A., Ainscough, J.F.X., Copeland, N. and Coverley, D. (2007) Cancer-associated missplicing of exon 4 influences the subnuclear distribution of the DNA replication factor CIZ1. Human Mutation, 28 (10). pp. 993-1004. ISSN 1059-7794

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Abstract

Cip1-interacting zinc finger protein 1 (CIZ1, also known as CDKN1A-interacting zinc finger protein 1) stimulates initiation of mammalian DNA replication and is normally tethered to the nuclear matrix within DNA replication foci. Here, we show that an alternatively spliced human CIZ1 variant, lacking exon 4 ( E4), is misexpressed as a consequence of intronic mutation in Ewing tumor (ET) cell lines. In all ET lines tested, exon 4 is skipped and an upstream mononucleotide repeat element is expanded to contain up to 28 thymidines, compared to 16 in controls. In exon-trap experiments, a 24T variant produced three-fold more exon skipping than a 16T variant, demonstrating a direct effect on splicing. In functional assays, E4 protein retains replication activity, but fails to form subnuclear foci. Furthermore, coexpression of mouse E4 with Ciz1 prevents Ciz1 from localizing appropriately, having a dominant negative effect on foci formation. The data show that conditional exclusion of exon 4 influences the spatial distribution of the Ciz1 protein within the nucleus, and raise the possibility that CIZ1 alternative splicing could influence organized patterns of DNA replication.

Item Type: Article
Institution: The University of York
Academic Units: The University of York > Biology (York)
The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Genetics, Health and Therapeutics (LIGHT)
Depositing User: York RAE Import
Date Deposited: 28 May 2009 10:46
Last Modified: 29 Sep 2010 14:23
Published Version: http://dx.doi.org/10.1002/humu.20550
Status: Published
Publisher: John Wiley & Sons
Identification Number: 10.1002/humu.20550
URI: http://eprints.whiterose.ac.uk/id/eprint/6255

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