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
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.
. [J]. Frontiers of Chemical Science and Engineering, 2016, 10(2): 186-195.
Andrew Best,Katherine James,Gerald Hysenaj,Alison Tyson-Capper,David J. Elliott. Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1. Front. Chem. Sci. Eng., 2016, 10(2): 186-195.
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
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