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Molecular cloning and characterization of the human topoisomerase II alpha and II beta genes: evidence for isoform evolution through gene duplication

Lookup NU author(s): Professor Caroline Austin

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Abstract

Human DNA topoisomerase II is essential for chromosome segregation and is the target for several clinically important anticancer agents. It is expressed as genetically distinct alpha and beta isoforms encoded by the TOP2 alpha and TOP beta 2 genes that map to chromosomes 17q21-22 and 3p24, respectively. The genes display different patterns of cell cycle- and tissue-specific expression, with the a isoform markedly upregulated in proliferating cells. In addition to the fundamental role of TOP2 alpha and TOP2 beta genes in cell growth and development, altered expression and rearrangement of both genes are implicated in anticancer drug resistance. Here, we report the complete structure of the human topoisomerase II alpha gene, which consists of 35 exons spanning 27.5 kb. Sequence data for the exon-intron boundaries were determined and examined in the context of topoisomerase II alpha protein structure comprising three functional domains associated with energy transduction, DNA breakage-reunion activity and nuclear localization. The organization of the 3' half of human TOP2 beta, including sequence specifying the C-terminal nuclear localization domain, was also elucidated. Of the 15 introns identified in this 20 kb region of TOP2 beta, the first nine and the last intron align in identical positions and display the same phases as introns in TOP2 alpha. Though their extreme 3' ends differ, the striking conservation suggests the two genes diverged recently in evolutionary terms consistent with a gene duplication event. Access to TOP2 alpha and TOP2 beta gene structures should aid studies of mutations and gene rearrangements associated with anticancer drug resistance. (C) 1999 Elsevier Science B.V. All rights reserved.


Publication metadata

Author(s): Austin CA; Sng JH; Heaton VJ; Bell M; Maini P; Fisher LM

Publication type: Article

Publication status: Published

Journal: Biochimica et Biophysica Acta: Gene Structure and Expression

Year: 1999

Volume: 1444

Issue: 3

Pages: 395-406

Print publication date: 24/03/1999

ISSN (print): 1874-9399

ISSN (electronic):

Publisher: Elsevier BV

URL: http://dx.doi.org/10.1016/S0167-4781(99)00020-2

DOI: 10.1016/S0167-4781(99)00020-2


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