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Frontiers of Chemical Science and Engineering

ISSN 2095-0179

ISSN 2095-0187(Online)

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Front. Chem. Sci. Eng.    2016, Vol. 10 Issue (2) : 186-195    https://doi.org/10.1007/s11705-015-1540-4
REVIEW ARTICLE
Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1
Andrew Best1,Katherine James2,Gerald Hysenaj1,Alison Tyson-Capper3,David J. Elliott1,*()
1. Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, UK
2. Interdisciplinary Computing and Complex BioSystems Research Group and Centre for Bacterial Cell Biology, Newcastle University, Newcastle NE1 3BZ, UK
3. Institute for Cellular Medicine, Newcastle University, Newcastle NE2 4HH, UK
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Abstract

Increased expression levels of the RNA splicing regulator Transformer2β (abbreviated Tra2β) have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2β and the highly similar Tra2α 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 Tra2β reduces splicing inclusion of a poison exon in the mRNA encoding Tra2α, thereby up-regulating Tra2α protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2β 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.
Keywords RNA splicing      gene expression      breast cancer      DNA damage      CHK1     
Corresponding Author(s): David J. Elliott   
Online First Date: 06 November 2015    Issue Date: 19 May 2016
 Cite this article:   
Andrew Best,Katherine James,Gerald Hysenaj, et al. Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1[J]. Front. Chem. Sci. Eng., 2016, 10(2): 186-195.
 URL:  
https://academic.hep.com.cn/fcse/EN/10.1007/s11705-015-1540-4
https://academic.hep.com.cn/fcse/EN/Y2016/V10/I2/186
Fig.1  Tra2α and Tra2β proteins have a similar modular structures. These comprise separate N-terminal and C-terminal regions containing a number of RS (arginine-serine residue) dipeptides; a single central RNA recognition motif (RRM); and a glycine hinge in between the RRM and C-terminal RS domain. The RRM is important to bind to target RNAs. Target RNA sequences are enriched in AGAA or CAA nucleotide sequences, and include CHK1 exon 3. The RS domains are likely involved in protein-protein interactions, including with components of the spliceosome
Some known protein interactions with Tra2β Reference
SAFB1/SAFB2 http://www.uniprot.org/uniprot/P62995
SNRNP70, SNRNPA1, SRRM [16]
SFRS4, SFRS55, SFRS6, SFRS9 http://www.uniprot.org/uniprot/P62995
CPSF6 [17]
RBMY [18]
RBMX [19]
RNPS1 [20]
SRSF13A [21]
Tab.1  Some known protein interaction partners for Tra2βa)
Fig.2  Tra2β binds to poison exons in the Tra2b and Tra2a genes. Tra2β binding sites were identified by iCLIP [27], and mapped onto the human genome. This screenshot from the UCSC genome browser shows high densities of Tra2β binding sites specifically above the poison exons within these genes [28]
Fig.3  Feedback control between Tra2α and Tra2β proteins buffers splicing changes when just one protein is depleted. There are two Tra2 proteins encoded in the human genome. Evidence in MDA-MB-231 cells shows that steady state levels of Tra2 proteins are maintained by feedback control mechanisms through splicing of poison exons (full details in text) [27]. In MDA-MB-231 breast cancer cells, higher levels of Tra2β efficiently repress Tra2α protein expression. Joint depletion of Tra2α and Tra2β has revealed splicing defects in important genes, and results in a block in cell proliferation
Fig.4  Tra2β binds to exon 3 of CHK1 and controls its splicing inclusion. This shows a picture of iCLIP tags to human Tra2β mapped back to the human genome sequence on the UCSC genome browser. This screenshot was downloaded from the UCSC genome browser [28], and shows the CHK1 gene and adjacent ACRV1 gene (since one of the annotated mRNA isoforms from the CHK1 gene actually extends into the ACRV1 gene)
Gene Connection with cancer Reference
CHK1 G2 and S phase checkpoint that is essential in many cancer cells to prevent damaged chromosomes from entering mitosis [38]
Vigilin (HDLBP) Represses proto-oncogene c-fms in breast cancer [43–45]
KDM5A, KDM3A Histone methylases, erase epigenetic information, tumour promoters [46,47]
NCOA Chromatin remodeling protein involved in breast cancer [48]
ATRX Frequently mutated in paediatric cancer [49]
SMC4 Key role in lung cancer, over-expressed in liver cancer [50,51]
Nap1L1 Cooperates with Myc to promote tumourigenesis [52]
NASP Cancer and embryonic isoform of histone chaperone that might be needed during conditions of rapid replication Reviewed by [12]
PRM2 Associated with tumour grade and expression of cyclin D1 in breast cancer [53]
SMYD2 Methylates and promotes activity of PARP1, methylates estrogen receptor, over-expression linked to poor leukaemia prognosis [54–56]
CDCA7L cMYC interacting protein [57]
KIF14 Involved in chemoresistance and AKT activity in triple negative breast cancer cells [58,59]
CCNL1 Cyclin L1, over-expressed in breast cancer, and over-expression linked to prognosis in cervical cancer [60,61]
NUB1 Negative regulator of NEDD8 and potential target for cancer therapy [62]
ANLN Mitogen activated protein kinase, increased expression poor prognostic marker in breast cancer [63]
NIPBL Cohesion loading complex protein associated with tamoxifen resistance in breast cancer [64]
VAPB Regulates breast cancer proliferation through Akt [65]
PDCD6IP Programmed Cell Death Interacting Protein, suggested prognostic marker in breast cancer [66]
AnkRD1 High expression involved in cisplatin resistance in ovarian cancer [67]
PAM Secreted into media by prostate and lung cancer cells [68]
IWS1 Involved in switching FGFR2 splicing to more tumorigenic isoform [69]
ZCCHC11 Promotes tumour growth and metastasis, over-expressed in cancers [70]
Tab.2  Some exons that are under joint control by Tra2α and Tra2β in the breast cancer cell line MDA-MB-231a)
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