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Cancer‐associated missplicing of exon 4 influences the subnuclear distribution of the DNA replication factor CIZ1
Author(s) -
Rahman Faisal Abdel,
Ainscough Justin F.X.,
Copeland Nikki,
Coverley Dawn
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20550
Subject(s) - exon , biology , dna replication , replication factor c , origin recognition complex , rna splicing , zinc finger , nuclear matrix , microbiology and biotechnology , dna replication factor cdt1 , alternative splicing , eukaryotic dna replication , nuclear protein , dna , genetics , transcription factor , gene , rna , chromatin
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 (Δ 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, Δ E4 protein retains replication activity, but fails to form subnuclear foci. Furthermore, coexpression of mouse Δ 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. Hum Mutat 28(10), 993–1004, 2007. © 2007 Wiley‐Liss, Inc.