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Frontiers of Chemical Science and Engineering >> 2016, Volume 10, Issue 2 doi: 10.1007/s11705-015-1540-4

Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1

. Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, UK.. Interdisciplinary Computing and Complex BioSystems Research Group and Centre for Bacterial Cell Biology, Newcastle University, Newcastle NE1 3BZ, UK.. Institute for Cellular Medicine, Newcastle University, Newcastle NE2 4HH, UK

Accepted: 2015-11-06 Available online: 2016-05-19

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Abstract

Increased expression levels of the RNA splicing regulator Transformer2 (abbreviated Tra2 ) have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2 and the highly similar Tra2 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 reduces splicing inclusion of a poison exon in the mRNA encoding Tra2 , thereby up-regulating Tra2 protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2 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.

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