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Lookup NU author(s): Dr Andrew Best,
Dr Katherine James,
Professor Alison Tyson-Capper,
Professor David Elliott
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Increased expression levels of the RNA splicing regulator Transformer2 beta (abbreviated Tra2 beta) have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2 beta and the highly similar Tra2 alpha protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2 beta reduces splicing inclusion of a poison exon in the mRNA encoding Tra2 alpha, thereby up-regulating Tra2 alpha protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2 beta alone. Discovery of this cross-regulation pathway, and its by-pass by joint depletion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 (CHK1) gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.
Author(s): Best A, James K, Hysenaj G, Tyson-Capper A, Elliott DJ
Publication type: Review
Publication status: Published
Journal: Frontiers of Chemical Science and Engineering
Print publication date: 01/06/2016
Online publication date: 05/11/2015
Acceptance date: 27/09/2015
ISSN (print): 2095-0179
ISSN (electronic): 2095-0187