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

Biomedical and Life Sciences

Text available via DOI:

https://doi.org/10.1002/humu.20550
Final published version

Keywords

DNA replication, Ciz1, Alternative splicing, Ewing tumour

View graph of relations

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Published

Standard

Cancer-associated missplicing of exon 4 influences the subnuclear distribution of the DNA replication factor CIZ1. / Rahman, Faisal Abdul; Ainscough, Justin F X ; Copeland, Nikki et al.
In: Human Mutation, Vol. 28, No. 10, 10.2007, p. 993-1004.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Bibtex

@article{9ae695571f4b4879b9daf7649a50b0f4,

title = "Cancer-associated missplicing of exon 4 influences the subnuclear distribution of the DNA replication factor CIZ1.",

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 (Delta 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, Delta E4 protein retains replication activity, but fails to form subnuclear foci. Furthermore, coexpression of mouse Delta 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.",

keywords = " DNA replication, Ciz1, Alternative splicing, Ewing tumour",

author = "Rahman, {Faisal Abdul} and Ainscough, {Justin F X} and Nikki Copeland and Dawn Coverley",

year = "2007",

month = oct,

doi = "10.1002/humu.20550",

language = "English",

volume = "28",

pages = "993--1004",

journal = "Human Mutation",

issn = "1098-1004",

publisher = "Wiley-Liss Inc.",

number = "10",

}

RIS

TY - JOUR

T1 - Cancer-associated missplicing of exon 4 influences the subnuclear distribution of the DNA replication factor CIZ1.

AU - Rahman, Faisal Abdul

AU - Ainscough, Justin F X

AU - Copeland, Nikki

AU - Coverley, Dawn

PY - 2007/10

Y1 - 2007/10

N2 - 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 (Delta 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, Delta E4 protein retains replication activity, but fails to form subnuclear foci. Furthermore, coexpression of mouse Delta 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.

AB - 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 (Delta 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, Delta E4 protein retains replication activity, but fails to form subnuclear foci. Furthermore, coexpression of mouse Delta 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.

KW - DNA replication

KW - Ciz1

KW - Alternative splicing

KW - Ewing tumour

U2 - 10.1002/humu.20550

DO - 10.1002/humu.20550

M3 - Journal article

VL - 28

SP - 993

EP - 1004

JO - Human Mutation

JF - Human Mutation

SN - 1098-1004

IS - 10

ER -

Research

Links

Text available via DOI:

Keywords